Pyrido- and pyrimidopyrimidine derivatives as anti-profilerative agents

ABSTRACT

The present invention concerns the compounds of formula 
     
       
         
         
             
             
         
       
         
         
           
             wherein 
             a 1 -a 2 =a 3 -a 4  represents a divalent radical selected from N—CH═CH—CH, N—CH═N—CH or CH—CH═N—CH; 
             Z represents NH; Y represents —C 3-9 alkyl-, —C 1-5 alkyl-NR 13 —C 1-5 alkyl-, —C 1-6  alkyl-NH—CO— or —CO—NH—C 1-6 alkyl-; 
             X 1  represents —O— or —NR 11 —; X 2  represents —C 1-2 alkyl-, —O—C 1-2 alkyl, —O— or —O—CH 2 —; 
             R 1  represents hydrogen or halo; 
             R 2  represents hydrogen, cyano, halo, hydroxycarbonyl-, C 1-4 alkyloxycarbonyl-, Het 16 -carbonyl- or Ar 5 ; 
             R 3  represents hydrogen; 
             R 4  represents hydroxy, C 1-4 alkyloxy-, Ar 4 —C 1-4 alkyloxy or substituted C 1-4 alkyloxy; 
             R 11  represents hydrogen; 
             R 12  represents hydrogen, C 1-4 alkyl- or C 1-4 alkyl-oxy-carbonyl-; 
             R 13  represents morpholinyl-C 1-4 alkyl; 
             Het 2  represents morpholinyl or piperidinyl optionally substituted with C 1-4 alkyl-, preferably methyl; 
             Het 14  represents morpholinyl; 
             Het 16  represents morpholinyl or pyrrolidinyl; 
             Ar 4  represents phenyl; 
             Ar 5  represents phenyl optionally substituted with cyano.

This invention relates to pyrimidopyrimidine derived macrocycles thathave been found to possess anti-proliferative activity, such asanti-cancer activity and are accordingly useful in methods of treatmentof the human or animal body, for example in the manufacture ofmedicaments for use in hyper proliferative disorders such asatherosclerosis, restenosis and cancer. The invention also relates toprocesses for the manufacture of said pyrimidopyrimidine derivatives, topharmaceutical compositions containing them and to their use in themanufacture of medicaments of use in the production ofanti-proliferative effect.

In particular, the compounds of the present invention were found toinhibit tyrosine kinase enzymes, also called tyrosine kinases. Tyrosinekinases are a class of enzymes, which catalyse the transfer of theterminal phosphate of adenosine triphosphate to the phenolic hydroxylgroup of a tyrosine residue present in the target protein. It is known,that several oncogenes, involved in the transformation of a cell into amalignant tumour cell, encode tyrosine kinase enzymes including certaingrowth factor receptors such as EGF, FGF, IGF-1R, IR, PDGF and VEGF.This family of receptor tyrosine kinases and in particular the EGFfamily of receptor tyrosine kinases are frequently present in commonhuman cancers such as breast cancer, non-small cell lung cancersincluding adenocarcinomas and squamous cell cancer of the lung, bladdercancer, oesophageal cancer, gastrointestinal cancer such as colon,rectal or stomach cancer, cancer of the prostate, leukaemia and ovarian,bronchial or pancreatic cancer, which are examples of cell proliferationrelated disorders.

Accordingly, it has been recognised that the selective inhibition oftyrosine kinases will be of value in the treatment of cell proliferationrelated disorders. Support for this view is provided by the developmentof Herceptin® (Trastuzumab) and Gleevec™ (imatinib mesylate) the firstexamples of target based cancer drugs. Herceptin® (Trastuzumab) istargeted against Her2/neu, a receptor tyrosine kinase found to beamplified up to 100-fold in about 30% of patients with invasive breastcancer. In clinical trials Herceptin® (Trastuzumab) proved to haveanti-tumour activity against breast cancer (Review by L. K. Shawer etal, “Smart Drugs: Tyrosine kinase inhibitors in cancer therapy”, 2002,Cancer Cell Vol. 1, 117), and accordingly provided the proof ofprinciple for therapy targeted to receptor tyrosine kinases. The secondexample, Gleevec™ (imatinib mesylate), is targeted against the abelsontyrosine kinase (BcR-Abl), a constitutively active cytoplasmic tyrosinekinase present in virtually all patients with chronic myelogenousleukaemia (CML) and 15% to 30% of adult patients with acutelymphoblastic leukaemia. In clinical trials Gleevec™ (imatinib mesylate)showed a spectacular efficacy with minimal side effects that led to anapproval within 3 months of submission. The speed of passage of thisagent through clinical trials and regulatory review has become a casestudy in rapid drug development (Drucker B. J. & Lydon N., “Lessonslearned from the development of an Abl tyrosine kinase inhibitor forchronic myelogenous leukaemia.”, 2000, J. Clin. Invest. 105, 3).

Further support is given by the demonstration that EGF receptor tyrosinekinase inhibitors, specifically attenuates the growth in athymic nudemice of transplanted carcinomas such as human mammary carcinoma or humansquamous cell carcinoma (Review by T. R. Burke Jr., Drugs of the Future,1992, 17, 119). As a consequence, there has been considerable interestin the development of drugs to treat different cancers that target theEGFR receptor. For example, several antibodies that bind to theextra-cellular domain of EGFR are undergoing clinical trials, includingErbitux™ (also called C225, Cetuximab), which was developed by ImcloneSystems and is in Phase III clinical trials for the treatment of severalcancers. Also, several promising orally active drugs that are potent andrelatively specific inhibitors of the EGFR tyrosine kinase are now welladvanced in clinical trials. The AstraZeneca compound ZD1839, which isnow called IRESSA® and approved for the treatment of advancednon-small-cell lung cancer, and the OSI/Genentech/Roche compoundOSI-774, which is now called Tarceva™ (erlotinib), have shown markedefficacy against several cancers in human clinical trials (Morin M. J.,“From oncogene to drug: development of small molecule tyrosine kinaseinhibitors as anti-tumour and anti-angiogenic agents, 2000, Oncogene 19,6574).

In addition to the above, EGF receptor tyrosine kinases has been shownto be implicated in non-malignant proliferative disorders such aspsoriasis (elder et al., Science, 1989, 243; 811). It is thereforeexpected that inhibitors of EGF type receptor tyrosine kinases will beuseful in the treatment of non-malignant diseases of excessive cellularproliferation such as psoriasis, benign prostatic hypertrophy,atherosclerosis and restenosis.

It is disclosed in International Patent Applications WO 96/07657 &WO97/32880 that pyrimidopyrimidines are useful as inhibitors of tyrosinekinase and in particular of the EGF type receptor tyrosine kinases.Unexpectedly it was found that pyrimidopyrimidine derivatives of thepresent formula (I) that are different in structure show to havetyrosine kinase inhibitory activity.

It is accordingly an object of the present invention to provide furthertyrosine kinase inhibitors useful in the manufacture of medicaments inthe treatment of cell proliferative related disorders.

This invention concerns compounds of formula (I)

the N-oxide forms, the pharmaceutically acceptable addition salts andthe stereochemically isomeric forms thereof, wherein

-   a¹-a²=a³-a⁴ represents a divalent radical selected from N—CH═CH—CH,    N—CH═N—CH or CH—CH═N—CH;-   Z represents O, NH or S;-   Y represents —C₃₋₉alkyl-, —C₃₋₉alkenyl-, —C₁₋₅alkyl-oxy-C₁₋₅alkyl-,    —C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-, —C₁₋₅alkyl-NR¹⁴—CO—C₁₋₅alkyl-,    —C₁₋₅alkyl-CO—NR¹⁵—C₁₋₅alkyl-, —C₁₋₆alkyl-CO—NH—, —C₁₋₆alkyl-NH—CO—,    —CO—NH—C₁₋₆alkyl-, —NH—CO—C₁₋₆alkyl-, —CO—C₁₋₇alkyl-,    —C₁₋₇alkyl-CO—, C₁₋₆alkyl-CO—C₁₋₆alkyl;-   X¹ represents a direct bond, O, —O—C₁₋₂alkyl-, CO, —CO—C₁₋₂alkyl-,    NR¹¹, —NR¹¹—C₁₋₂alkyl-, NR¹⁶—CO—, NR¹⁶—CO—C₁₋₂alkyl-, —O—N═CH— or    C₁₋₂alkyl;-   X² represents a direct bond, O, —O—C₁₋₂alkyl-, CO, —CO—C₁₋₂alkyl-,    NR¹², NR¹²—C₁₋₂alkyl-, NR¹⁷—CO—, NR¹⁷—CO—C₁₋₂alkyl-,    Het²⁰-C₁₋₂alkyl-, —O—N═CH— or C₁₋₂alkyl;-   R¹ represents hydrogen, cyano, halo, hydroxy, formyl, C₁₋₆alkoxy-,    C₁₋₆alkyl-, C₁₋₆alkoxy- substituted with halo,    -   C₁₋₄alkyl substituted with one or where possible two or more        substituents selected from hydroxy or halo;-   R² represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-,    Het¹⁶-carbonyl-, C₁₋₄alkyloxycarbonyl-, C₁₋₄alkylcarbonyl-,    aminocarbonyl-, mono- or di(C₁₋₄alkyl)aminocarbonyl-, Het¹, formyl,    C₁₋₄alkyl-, C₂₋₆alkynyl-, C₃₋₆cycloalkyl-, C₃₋₆cycloalkyloxy-,    C₁₋₆alkoxy-, Ar⁵, Ar¹-oxy-, dihydroxyborane,    -   C₁₋₆alkoxy- substituted with halo,    -   C₁₋₄alkyl substituted with one or where possible two or more        substituents selected from halo, hydroxy or NR⁵R⁶,    -   C₁₋₄alkylcarbonyl- wherein said C₁₋₄alkyl is optionally        substituted with one or where possible two or more substituents        selected from hydroxy or C₁₋₄alkyl-oxy-;-   R³ represents hydrogen, C₁₋₄alkyl, cyano or C₁₋₄alkyl substituted    with one or more substituents selected from halo, C₁₋₄alkyloxy-,    amino-, mono- or di(C₁₋₄alkyl)amino-, C₁₋₄alkyl-sulfonyl- or phenyl;-   R⁴ represents hydrogen, hydroxy, Ar³-oxy, Ar⁴—C₁₋₄alkyloxy-,    C₁₋₄alkyloxy-, C₂₋₄alkenyloxy- optionally substituted with Het¹² or    R⁴ represents C₁₋₄alkyloxy substituted with one or where possible    two or more substituents selected from C₁₋₄alkyloxy-, hydroxy, halo,    Het²-, —NR⁷R⁸, -carbonyl-NR⁹R¹⁰ or Het³-carbonyl-;-   R⁵ and R⁶ are each independently selected from hydrogen or    C₁₋₄alkyl;-   R⁷ and R⁸ are each independently selected from hydrogen, C₁₋₄alkyl,    Het⁸, aminosulfonyl-, mono- or di(C₁₋₄alkyl)-aminosulfonyl,    hydroxy-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-,    hydroxycarbonyl-C₁₋₄alkyl-, C₃₋₆cycloalkyl,    Het⁹-carbonyl-C₁₋₄alkyl-, Het¹⁰-carbonyl-, polyhydroxy-C₁₋₄alkyl-,    Het¹¹-C₁₋₄alkyl- or Ar²—C₁₋₄alkyl-;-   R⁹ and R¹⁰ are each independently selected from hydrogen, C₁₋₄alkyl,    C₃₋₆cycloalkyl, Het⁴, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl- or    polyhydroxy-C₁₋₄alkyl-;-   R¹¹ represents hydrogen, C₁₋₄alkyl, Het⁵, Het⁶-C₁₋₄alkyl-,    C₂₋₄alkenylcarbonyl-optionally substituted with    Het⁷-C₁₋₄alkylaminocarbonyl-, C₂₋₄alkenylsulfonyl-,    C₁₋₄alkyloxyC₁₋₄alkyl- or phenyl optionally substituted with one or    where possible two or more substituents selected from hydrogen,    hydroxy, amino or C₁₋₄alkyloxy-;-   R¹² represents hydrogen, C₁₋₄alkyl, C₁₋₄alkyl-oxy-carbonyl-, Het¹⁷,    Het¹⁸-C₁₋₄alkyl-, C₂₋₄alkenylcarbonyl- optionally substituted with    Het¹⁹-C₁₋₄alkylaminocarbonyl-, C₂₋₄alkenylsulfonyl-,    C₁₋₄alkyloxyC₁₋₄alkyl- or phenyl optionally substituted with one or    where possible two or more substituents selected from hydrogen,    hydroxy, amino or C₁₋₄alkyloxy-;-   R¹³ represents hydrogen, C₁₋₄alkyl, Het¹³, Het¹⁴-C₁₋₄alkyl- or    phenyl optionally substituted with one or where possible two or more    substituents selected from hydrogen, hydroxy, amino or    C₁₋₄alkyloxy-;-   R¹⁴ and R¹⁵ are each independently selected from hydrogen,    C₁₋₄alkyl, Het¹⁵-C₁₋₄alkyl- or C₁₋₄alkyloxyC₁₋₄alkyl-;-   R¹⁶ and R¹⁷ are each independently selected from hydrogen,    C₁₋₄alkyl, Het²¹-C₁₋₄alkyl- or C₁₋₄alkyloxyC₁₋₄alkyl-;-   Het¹ represents a heterocycle selected from piperidinyl,    morpholinyl, piperazinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl,    oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or    pyrrolidinyl wherein said Het¹ is optionally substituted with one or    where possible two or more substituents selected from amino,    C₁₋₄alkyl, hydroxy-C₁₋₄alkyl-, phenyl, phenyl-C₁₋₄alkyl-,    C₁₋₄alkyl-oxy-C₁₋₄alkyl- mono- or di(C₁₋₄alkyl)amino- or    amino-carbonyl-;-   Het² represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl or dithianyl    wherein said Het² is optionally substituted with one or where    possible two or more substituents selected from hydroxy, halo,    amino, C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-,    hydroxy-C₁₋₄alkyl-oxy-C₁₋₄alkyl-, mono- or di(C₁₋₄alkyl)amino-,    mono- or di(C₁₋₄alkyl)amino-C₁₋₄alkyl-, aminoC₁₋₄alkyl-, mono- or    di(C₁₋₄alkyl)amino-sulfonyl-, aminosulfonyl-;-   Het³, Het⁴ and Het⁸ each independently represent a heterocycle    selected from morpholinyl, piperazinyl, piperidinyl, furanyl,    pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl,    oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het³, Het⁴ or    Het⁸ is optionally substituted with one or where possible two or    more substituents selected from hydroxy-, amino-, C₁₋₄alkyl-,    C₃₋₆cycloalkyl-C₁₋₄alkyl-, aminosulfonyl-, mono- or    di(C₁₋₄alkyl)aminosulfonyl or amino-C₁₋₄alkyl-;-   Het⁵ represent a heterocycle selected from pyrrolidinyl or    piperidinyl wherein said heterocycle is optionally substituted with    one or where possible two or more substituents selected from    C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl    or polyhydroxy-C₁₋₄alkyl-;-   Het⁶ and Het⁷ each independently represent a heterocycle selected    from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl wherein    said Het⁶ or Het⁷ is optionally substituted with one or where    possible two or more substituents selected from C₁₋₄alkyl,    C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or    polyhydroxy-C₁₋₄alkyl-;-   Het⁹ and Het¹⁰ each independently represent a heterocycle selected    from furanyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl,    dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl,    oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het⁹ or Het¹⁰ is    optionally substituted C₁₋₄alkyl, C₃₋₆cycloalkyl-C₁₋₄alkyl- or    amino-C₁₋₄alkyl-;-   Het¹¹ represents a heterocycle selected from indolyl or

-   Het¹² represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl or dithianyl    wherein said Het¹² is optionally substituted with one or where    possible two or more substituents selected from hydroxy, halo,    amino, C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-,    hydroxy-C₁₋₄alkyl-oxy-C₁₋₄alkyl-, mono- or di(C₁₋₄alkyl)amino- or    mono- or di(C₁₋₄alkyl)amino-C₁₋₄alkyl-;-   Het¹³ represent a heterocycle selected from pyrrolidinyl or    piperidinyl wherein said heterocycle is optionally substituted with    one or where possible two or more substituents selected from    C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄allyl-, C₁₋₄alkyloxyC₁₋₄alkyl    or polyhydroxy-C₁₋₄alkyl-;-   Het¹⁴ represent a heterocycle selected from morpholinyl,    pyrrolidinyl, piperazinyl or piperidinyl wherein said heterocycle is    optionally substituted with one or where possible two or more    substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl,    hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-;

Het¹⁵ and Het²¹ each independently represent a heterocycle selected frommorpholinyl, pyrrolidinyl, piperazinyl or piperidinyl wherein said Het¹⁵or Het²¹ are optionally substituted with one or where possible two ormore substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl,hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-;

-   Het¹⁶ represent a heterocycle selected from morpholinyl,    pyrrolidinyl, piperazinyl, 1,3,2-dioxaborolane or piperidinyl    wherein said heterocycle is optionally substituted with one or more    substituents selected from C₁₋₄alkyl;-   Het¹⁷ represent a heterocycle selected from pyrrolidinyl or    piperidinyl wherein said heterocycle is optionally substituted with    one or where possible two or more substituents selected from    C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl    or polyhydroxy-C₁₋₄alkyl-;-   Het¹⁸ and Het¹⁹ each independently represent a heterocycle selected    from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl wherein    said Het¹⁸ and Het¹⁹ are optionally substituted with one or where    possible two or more substituents selected from C₁₋₄alkyl,    C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or    polyhydroxy-C₁₋₄alkyl-;-   Het²⁰ represents a heterocycle selected from pyrrolidinyl,    2-pyrrolidinyl, piperidinyl, piperazinyl or pyrazolidinyl wherein    said heterocycle is optionally substituted with one or where    possible two or more substituents selected from C₁₋₄alkyl,    C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or    polyhydroxy-C₁₋₄alkyl-; and-   Ar¹, Ar², Ar³, Ar⁴ and Ar⁵ each independently represent phenyl    optionally substituted with cyano, C₁₋₄alkylsulfonyl-,    C₁₋₄alkylsulfonylamino-, aminosulfonylamino-, hydroxy-C₁₋₄alkyl,    aminosulfonyl-, hydroxy-, C₁₋₄alkyloxy- or C₁₋₄alkyl.    As used in the foregoing definitions and hereinafter,

halo is generic to fluoro, chloro, bromo and iodo;

C₁₋₂alkyl defines methyl or ethyl;

C₁₋₃alkyl defines straight and branched chain saturated hydrocarbonradicals having from 1 to 3 carbon atoms such as, for example, methyl,ethyl, propyl and the like;

C₁₋₄alkyl defines straight and branched chain saturated hydrocarbonradicals having from 1 to 4 carbon atoms such as, for example, methyl,ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyland the like;

-   -   C₁₋₅alkyl defines straight and branched chain saturated        hydrocarbon radicals having from 1 to 5 carbon atoms such as,        for example, methyl, ethyl, propyl, butyl, pentyl,        1-methylbutyl, 2,2-dimethylpropyl, 2,2-dimethylethyl and the        like;

C₁₋₆alkyl is meant to include C₁₋₅alkyl and the higher homologuesthereof having 6 carbon atoms such as, for example hexyl,1,2-dimethylbutyl, 2-methylpentyl and the like;

C₁₋₇alkyl is meant to include C₁₋₆alkyl and the higher homologuesthereof having 7 carbon atoms such as, for example 1,2,3-dimethylbutyl,1,2-methylpentyl and the like;

C₃₋₉alkyl defines straight and branched chain saturated hydrocarbonradicals having from 3 to 9 carbon atoms such as propyl, butyl, pentyl,hexyl, heptyl, octyl, nonyl and the like;

C₂₋₄alkenyl defines straight and branched chain hydrocarbon radicalscontaining one double bond and having from 2 to 4 carbon atoms such as,for example vinyl, 2-propenyl, 3-butenyl, 2-butenyl and the like;

C₃₋₉alkenyl defines straight and branched chain hydrocarbon radicalscontaining one double bond and having from 3 to 9 carbon atoms such as,for example 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl,3-methyl-2-butenyl, 3-hexenyl and the like;

C₂₋₆alkynyl defines straight and branched chain hydrocarbon radicalscontaining one triple bond and having from 2 to 6 carbon atoms such as,for example, 2-propynyl, 3-butynyl, 2-butynyl, 2-pentynyl, 3-pentynyl,3-methyl-2-butynyl, 3-hexynyl and the like;

C₃₋₆cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl;

C₁₋₄alkyloxy defines straight or branched saturated hydrocarbon radicalssuch as methoxy, ethoxy, propyloxy, butyloxy, 1-methylethyloxy,2-methylpropyloxy and the like;

C₁₋₆alkyloxy is meant to include C₁₋₄alkyloxy and the higher homologuessuch as methoxy, ethoxy, propyloxy, butyloxy, 1-methylethyloxy,2-methylpropyloxy and the like;

polyhydroxy-C₁₋₄alkyl is generic to a C₁₋₄alkyl as defined hereinbefore,having two, three or were possible more hydroxy substituents, such asfor example trifluoromethyl.

As used in the foregoing definitions and hereinafter, the term formylrefers to a radical of formula —CH(═O). When X¹ or X² represents thedivalent radical —O—N═CH—, said radical is attached with the carbon atomto the R³, R⁴ bearing cyclic moiety, respectively the R¹, R² bearingphenyl moiety of the compounds of formula (I).

The heterocycles as mentioned in the above definitions and hereinafter,are meant to include all possible isomeric forms thereof, for instancepyrrolyl also includes 2H-pyrrolyl; triazolyl includes 1,2,4-triazolyland 1,3,4-triazolyl; oxadiazolyl includes 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl and 1,3,4-oxadiazolyl; thiadiazolylincludes 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl and1,3,4-thiadiazolyl; pyranyl includes 2H-pyranyl and 4H-pyranyl.

Further, the heterocycles as mentioned in the above definitions andhereinafter may be attached to the remainder of the molecule of formula(I) through any ring carbon or heteroatom as appropriate. Thus, forexample, when the heterocycle is imidazolyl, it may be a 1-imidazolyl,2-imidazolyl, 3-imidazolyl, 4-imidazolyl and 5-imidazolyl; when it isthiazolyl, it may be 2-thiazolyl, 4-thiazolyl and 5-thiazolyl; when itis triazolyl, it may be 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl,1,2,4-triazol-5-yl, 1,3,4-triazol-1-yl and 1,3,4-triazol-2-yl; when itis benzothiazolyl, it may be 2-benzothiazolyl, 4-benzothiazolyl,5-benzothiazolyl, 6-benzothiazolyl and 7-benzothiazolyl.

The pharmaceutically acceptable addition salts as mentioned hereinaboveare meant to comprise the therapeutically active non-toxic acid additionsalt forms which the compounds of formula (I) are able to form. Thelatter can conveniently be obtained by treating the base form with suchappropriate acid. Appropriate acids comprise, for example, inorganicacids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid;sulfuric; nitric; phosphoric and the like acids; or organic acids suchas, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic,oxalic, malonic, succinic (i.e. butane-dioic acid), maleic, fumaric,malic, tartaric, citric, methanesulfonic, ethanesulfonic,benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids.

The pharmaceutically acceptable addition salts as mentioned hereinaboveare meant to comprise the therapeutically active non-toxic base additionsalt forms which the compounds of formula (I) are able to form. Examplesof such base addition salt forms are, for example, the sodium,potassium, calcium salts, and also the salts with pharmaceuticallyacceptable amines such as, for example, ammonia, alkylamines,benzathine, N-methyl-D-glucamine, hydrabamine, amino acids, e.g.arginine, lysine.

Conversely said salt forms can be converted by treatment with anappropriate base or acid into the free acid or base form.

The term addition salt as used hereinabove also comprises the solvateswhich the compounds of formula (I) as well as the salts thereof, areable to form. Such solvates are for example hydrates, alcoholates andthe like.

The term stereochemically isomeric forms as used hereinbefore definesthe possible different isomeric as well as conformational forms whichthe compounds of formula (I) may possess. Unless otherwise mentioned orindicated, the chemical designation of compounds denotes the mixture ofall possible stereochemically and conformationally isomeric forms, saidmixtures containing all diastereomers, enantiomers and/or conformers ofthe basic molecular structure. All stereochemically isomeric forms ofthe compounds of formula (I) both in pure form or in admixture with eachother are intended to be embraced within the scope of the presentinvention.

Some of the compounds of formula (I) may also exist in their tautomericforms. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

The N-oxide forms of the compounds of formula (I) are meant to comprisethose compounds of formula (I) wherein one or several nitrogen atoms areoxidized to the so-called N-oxide.

A preferred group of compounds consists of those compounds of formula(I) wherein one or more of the following restrictions apply:

-   Z represents NH;-   Y represents —C₃₋₉alkyl-, —C₂₋₉alkenyl-, —C₁₋₅alkyl-oxy-C₁₋₅alkyl-,    —C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-, —C₁₋₆alkyl-NH—CO—, —CO—C₁₋₇alkyl-,    —C₁₋₇alkyl-CO— or C₁₋₆alkyl-CO—C₁₋₆alkyl;-   X¹ represents O, —O—C₁₋₂alkyl-, —O—N═CH—, NR¹¹ or —NR¹¹—C₁₋₂alkyl-;    in a particular embodiment X¹ represents —NR¹¹—, —O— or —O—CH₂—;-   X² represents a direct bond, O, —O—C₁₋₂alkyl-, —O—N═CH—, C₁₋₂alkyl,    NR¹² or NR¹²—C₁₋₂alkyl-; in a particular embodiment X² represents a    direct bond, —O—N═CH—, C₁₋₂alkyl-, —O—C₁₋₂alkyl, —O— or —O—CH₂—;-   R¹ represents hydrogen, cyano, halo or hydroxy, preferably halo;-   R² represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-,    C₁₋₄alkyloxycarbonyl-, Het¹⁶-carbonyl-, C₁₋₄alkyl-, C₂₋₆alkynyl-,    Ar⁵ or Het¹;    -   In a further embodiment R² represents hydrogen, cyano, halo,        hydroxy, or Ar⁵;-   R³ represents hydrogen;-   R⁴ represents hydrogen, hydroxy, C₁₋₄alkyloxy-, Ar⁴—C₁₋₄alkyloxy or    R⁴ represents C₁₋₄alkyloxy substituted with one or where possible    two or more substituents selected from    -   C₁₋₄alkyloxy- or Het²-;-   R¹¹ represents hydrogen, C₁₋₄alkyl- or C₁₋₄alkyl-oxy-carbonyl-;-   R¹² represents hydrogen, C₁₋₄alkyl- or C₁₋₄alkyl-oxy-carbonyl-;-   R¹³ represents Het¹⁴-C₁₋₄alkyl, in particular morpholinyl-C₁₋₄alkyl;-   Het¹ represents thiazolyl optionally substituted with amino,    C₁₋₄alkyl, hydroxy-C₁₋₄alkyl-, phenyl, phenyl-C₁₋₄alkyl-,    C₁₋₄alkyl-oxy-C₁₋₄alkyl-, mono- or di(C₁₋₄alkyl)amino- or    amino-carbonyl-;-   Het² represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl or pyrrolidinyl wherein said Het² is    optionally substituted with one or where possible two or more    substituents selected from hydroxy, amino or C₁₋₄alkyl-;    -   In a further embodiment Het² represents a heterocycle selected        from morpholinyl or piperidinyl optionally substituted with        C₁₋₄alkyl-, preferably methyl;-   Het¹⁴ represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl or pyrrolidinyl wherein said Het¹⁴ is    optionally substituted with one or where possible two or more    substituents selected from hydroxy, amino or C₁₋₄alkyl-;-   Het¹⁶ represents a heterocycle selected from piperidinyl,    morpholinyl or pyrrolidinyl;-   Ar⁴ represents phenyl optionally substituted with cyano, hydroxy-,    C₁₋₄alkyloxy or C₁₋₄alkyl;

Ar⁵ represents phenyl optionally substituted with cyano, hydroxy,C₁₋₄alkyloxy or C₁₋₄alkyl.

A further group of compounds consists of those compounds of formula (I)wherein one or more of the following restrictions apply:

-   Z represents NH;-   Y represents —C₃₋₉alkyl-, —C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-,    —C₁₋₆alkyl-NH—CO— or —CO—NH—C₁₋₆alkyl-;-   X¹ represents —O— or —NR¹¹—;-   X² represents a direct bond, —C₁₋₂alkyl-, —O—C₁₋₂alkyl, —O— or    —O—CH₂—;-   R¹ represents hydrogen or halo;-   R² represents hydrogen, cyano, halo, hydroxycarbonyl-,    C₁₋₄alkyloxycarbonyl-, Het¹⁶-carbonyl- or Ar⁵;-   R³ represents hydrogen;-   R⁴ represents hydrogen, hydroxy, C₁₋₄alkyloxy-, Ar⁴-C₁₋₄alkyloxy or    R⁴ represents C₁₋₄alkyloxy substituted with one or where possible    two or more substituents selected from    -   C₁₋₄alkyloxy- or Het²-;-   R¹¹ represents hydrogen;-   R¹² represents hydrogen, C₁₋₄alkyl- or C₁₋₄alkyl-oxy-carbonyl-;-   R¹³ represents Het¹⁴-C₁₋₄alkyl, in particular morpholinyl-C₁₋₄alkyl;-   Het² represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl or pyrrolidinyl wherein said Het² is    optionally substituted with one or where possible two or more    substituents selected from hydroxy, amino or C₁₋₄alkyl-;    -   In a further embodiment Het² represents a heterocycle selected        from morpholinyl or piperidinyl optionally substituted with        C₁₋₄alkyl-, preferably methyl;-   Het¹⁴ represents morpholinyl;-   Het¹⁶ represents a heterocycle selected from morpholinyl or    pyrrolidinyl;-   Ar⁴ represents phenyl;-   Ar⁵ represents phenyl optionally substituted with cyano.

Another group of compounds consists of those compounds of formula (I)wherein one or more of the following restrictions apply:

-   Z represents NH;-   Y represents —C₃₋₉alkyl-, —C₂₋₉alkenyl-, —C₁₋₅alkyl-oxy-C₁₋₅alkyl-,    —C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-, —C₁₋₅alkyl-NR¹⁴—CO—C₁₋₅alkyl-,    —C₁₋₆alkyl-NH—CO—, —CO—C₁₋₇alkyl-, —C₁₋₇alkyl-CO— or    C₁₋₆alkyl-CO—C₁₋₆alkyl;-   X¹ represents O, —O—C₁₋₂alkyl-, —O—N═CH—, NR¹¹ or —NR¹¹—C₁₋₂alkyl-;    in a particular embodiment X¹ represents a direct bond, C₁₋₂alkyl-,    —O—C₁₋₂alkyl, —NR¹¹—, —O— or —O—CH₂—;-   X² represents a direct bond, O, —O—C₁₋₂alkyl-, —O—N═CH—, NR¹⁷—CO—,    NR¹⁷—CO—C₁₋₂alkyl-, C₁₋₂alkyl, Het²⁰-C₁₋₂alkyl-, NR¹² or    NR¹²—C₁₋₂alkyl-; in a particular embodiment X² represents a direct    bond, C₁₋₂alkyl-, —O—C₁₋₂alkyl, NR¹⁷—CO—, NR¹⁷—CO—C₁₋₂alkyl-,    Het²⁰-C₁₋₂alkyl-, —O— or —O—CH₂—;-   R¹ represents hydrogen, cyano, halo or hydroxy, preferably halo;-   R² represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-,    C₁₋₄alkyloxycarbonyl-, Het¹⁶-carbonyl-, C₁₋₄alkyl-, C₂₋₆alkynyl-,    Ar⁵ or Het¹; in a further embodiment R² represents hydrogen, cyano,    halo, hydroxy, or Ar⁵; in a more particular embodiment R² represents    hydrogen or halo;-   R³ represents hydrogen;-   R⁴ represents hydrogen, hydroxy, C₁₋₄alkyloxy-, Ar⁴—C₁₋₄alkyloxy or    R⁴ represents C₁₋₄alkyloxy substituted with one or where possible    two or more substituents selected from    -   C₁₋₄alkyloxy- or Het²-;-   R¹¹ represents hydrogen, C₁₋₄alkyl- or C₁₋₄alkyl-oxy-carbonyl-;-   R¹² represents hydrogen, C₁₋₄alkyl- or C₁₋₄alkyl-oxy-carbonyl-;-   R¹³ represents hydrogen or Het¹⁴-C₁₋₄alkyl, in particular    morpholinyl-C₁₋₄alkyl;-   R¹⁴ represents hydrogen or C₁₋₄alkyl;-   R¹⁷ represents hydrogen, C₁₋₄alkyl-, Het²¹-C₁₋₄alkyl or    C₁₋₄alkyl-oxy-C₁₋₄alkyl; in particular R¹² represents hydrogen or    C₁₋₄alkyl;-   Het¹ represents thiazolyl optionally substituted with amino,    C₁₋₄alkyl, hydroxy-C₁₋₄alkyl-, phenyl, phenyl-C₁₋₄alkyl-,    C₁₋₄alkyl-oxy-C₁₋₄alkyl-, mono- or di(C₁₋₄alkyl)amino- or    amino-carbonyl-;-   Het² represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl or pyrrolidinyl wherein said Het² is    optionally substituted with one or where possible two or more    substituents selected from hydroxy, amino or C₁₋₄alkyl-;    -   In a further embodiment Het² represents a heterocycle selected        from morpholinyl or piperidinyl optionally substituted with        C₁₋₄alkyl-, preferably methyl;-   Het¹⁴ represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl or pyrrolidinyl wherein said Het¹⁴ is    optionally substituted with one or where possible two or more    substituents selected from hydroxy, amino or C₁₋₄alkyl-;-   Het¹⁶ represents a heterocycle selected from piperidinyl,    morpholinyl or pyrrolidinyl;-   Het²⁰ represents a heterocycle selected from pyrrolidinyl,    2-pyrrolidinyl or piperidinyl;-   Het²¹ represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl or pyrrolidinyl wherein said Het² is    optionally substituted with one or where possible two or more    substituents selected from hydroxy, amino or C₁₋₄alkyl-;-   Ar⁴ represents phenyl optionally substituted with cyano, hydroxy-,    C₁₋₄alkyloxy or C₁₋₄alkyl;-   Ar⁵ represents phenyl optionally substituted with cyano, hydroxy,    C₁₋₄alkyloxy or C₁₋₄alkyl.

A further group of compounds consists of those compounds of formula (I)wherein one or more of the following restrictions apply:

-   Z represents NH;-   Y represents —C₃₋₉alkyl-, —C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-,    —C₁₋₅alkyl-NR¹⁴—CO—C₁₋₅alkyl-, —C₁₋₆alkyl-NH—CO— or    —CO—NH—C₁₋₆alkyl-;-   X¹ represents a direct bond, —C₁₋₂alkyl-, —O—C₁₋₂alkyl, —O—, —O—CH₂—    or —NR¹¹—;-   X² represents —O—, —O—C₁₋₂alkyl, —NR¹²—, NR¹²—C₁₋₂alkyl, —NR¹⁷—CO—,    NR¹⁷—CO—C₁₋₂alkyl or Het²⁰-C₁₋₂alkyl-;-   R¹ represents hydrogen or halo;-   R² represents hydrogen, cyano, halo, hydroxycarbonyl-,    C₁₋₄alkyloxycarbonyl-, Het¹⁶-carbonyl- or Ar⁵; in particular R²    represents hydrogen or halo;-   R³ represents hydrogen;-   R⁴ represents hydrogen, hydroxy, C₁₋₄alkyloxy-, Ar⁴—C₁₋₄alkyloxy or    R⁴ represents C₁₋₄alkyloxy substituted with one or where possible    two or more substituents selected from C₁₋₄alkyloxy- or Het²-;-   R¹¹ represents hydrogen;-   R¹² represents hydrogen, C₁₋₄alkyl- or C₁₋₄alkyl-oxy-carbonyl-;-   R¹³ represents hydrogen or Het¹⁴-C₁₋₄alkyl, in particular hydrogen    or morpholinyl-C₁₋₄alkyl;-   R¹⁴ represents hydrogen;-   R¹⁷ represents hydrogen;-   Het² represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl or pyrrolidinyl wherein said Het² is    optionally substituted with one or where possible two or more    substituents selected from hydroxy, amino or C₁₋₄alkyl-; In a    further embodiment Het² represents a heterocycle selected from    morpholinyl or piperidinyl optionally substituted with C₁₋₄alkyl-,    preferably methyl;-   Het¹⁴ represents morpholinyl;-   Het¹⁶ represents a heterocycle selected from morpholinyl or    pyrrolidinyl;-   Het²⁰ represents pyrrolidinyl or piperidinyl;-   Ar⁴ represents phenyl;-   Ar⁵ represents phenyl optionally substituted with cyano.

Other special group of compounds are:

-   -   those compounds of formula (I0 wherein a¹-a²=a³-a⁴ represents        N—CH═CH—CH;    -   those compounds of formula (I) wherein a¹-a²=a³-a⁴ represents        N—CH═N—CH;    -   those compounds of formula (I) wherein a¹-a²=a³-a⁴ represents        CH—CH═N—CH;    -   those compounds of formula (I) wherein —X¹— represents —O—;    -   those compounds of formula (I) wherein —X¹— represents —NR¹¹—,        in particular —NH—;    -   those compounds of formula (I) wherein —X²— represents        —NR¹⁷—CO—C₁₋₂alkyl-, in particular —NH—CO—C₁₋₂alkyl-;    -   those compounds of formula (I) wherein —X²— represents        —NR¹²—C₁₋₂alkyl, in particular —NH—C₁₋₂alkyl-;    -   those compounds of formula (I) wherein —Y— represents        —C₁₋₅alkyl-NR¹⁴—CO—C₁₋₅ alkyl-, in particular        —C₁₋₅alkyl-NH—CO—C₁₋₅alkyl-;    -   those compounds of formula (I) wherein R¹ is fluoro, chloro or        bromo;    -   those compounds of formula (I) wherein R² is fluoro, chloro or        bromo;    -   those compounds of formula (I) wherein R¹ and R² represent halo,        in particular those compounds of formula (I) wherein R¹        represents fluoro and R² represents chloro;    -   those compounds of formula (I) wherein R² is Het¹, in particular        thiazolyl optionally substituted with methyl;    -   those compounds of formula (I) wherein R² is C₂₋₆alkynyl-, in        particular ethylyn;    -   those compounds of formula (I) wherein R² is Ar⁵, in particular        phenyl optionally substituted with cyano;    -   those compounds of formula (I) wherein R³ is cyano;    -   those compounds of formula (I) wherein R⁴ represents methoxy and        wherein said methoxy is at position 7 of the structure of        formula (I).    -   those compounds of formula (I) wherein R⁴ represents        C₁₋₄alkyloxy substituted with one substituent selected from        C₁₋₄alkyloxy- or Het²-, in particular propyloxy substituted with        morpholinyl;    -   those compounds of formula (I) wherein R¹² is hydrogen or        C₁₋₄alkyl-, in particular methyl or wherein R¹² is        C₁₋₄alkyl-oxy-carbonyl-, in particular t-butyl-oxy-carbonyl-    -   those compounds of formula (I) wherein Het² represent        morpholinyl optionally substituted with C₁₋₄alkyl, preferably        morpholinyl attached through the nitrogen atom to the remainder        of the compounds of formula (I);    -   those compounds of formula (I) with Het³ represent morpholinyl        optionally substituted with C₁₋₄alkyl, preferably morpholinyl        attached through the nitrogen atom to the remainder of the        compounds of formula (I);    -   those compounds of formula (I) wherein Het¹² represent        morpholinyl optionally substituted with C₁₋₄alkyl, preferably        morpholinyl attached through the nitrogen atom to the remainder        of the compounds of formula (I).

In a further embodiment of the present invention the R¹ substituent isat position 4′, the R² substituent is at position 5′, the R³ substituentis at position 2 and the R⁴ substituent at position 6 of the structureof formula (I). A particular group of compounds according to the presentinvention are those compounds of formula (I) wherein the anilinefragment is substituted with an R² substituent at position 5′ and an R¹substituent at position 4′ and wherein said R¹ substituent representshalo, in particular fluoro and wherein said R² substituent is beingselected from the group consisting of halo, C₁₋₄alkyloxycarbonyl-,Het¹⁶-carbonyl-, hydroxycarbonyl-, cyano, or Ar^(y); in particular saidR² being selected from chloro, bromo, methoxycarbonyl,pyrrolidino-carbonyl, morpholino-carbonyl, hydroxycarbonyl, cyano orphenyl.

The compounds of this invention can be prepared by any of severalstandard synthetic processes commonly used by those skilled in the artof organic chemistry and described for instance in the followingreferences; “Heterocyclic Compounds”—Vol. 24 (part4) p 261-304 Fusedpyrimidines, Wiley-Interscience; Chem. Pharm. Bull., Vol 41(2) 362-368(1993); J. Chem. Soc., Perkin Trans. 1, 2001, 130-137.

In brief, for those compounds of formula (I) where —X¹— represents —NH—said compounds are generally prepared by reacting the4-chloro-6-fluoro-pyridopyrimidines or 4,6-dichloro-pyridopyrimidines offormula (II) with an appropriate aniline (III) using art known reactionconditions, such as for example using a base such as triethylamine,N-ethyl-N-(1-methylethyl)-2-propaneamine (DIPEA) and alike or aninorganic base such as Na₂CO₃, K₂CO₃ and alike in a suitable polarsolvent such as propane-2-ol, 1-butanol, acetonitrile and alike atelevated temperatures (60-90° C. or reflux temperatures). The thusobtained anilinopyridopyrimidens (IV) are in a further step substitutedby a suitable amine of formula (VII) to give the intermediate of formulaVIII. This second substitution reaction is performed under knownreactions conditions, such as for example, by stirring the reagentia atan elevated temperature (70-100° C.) optionally in an appropriatesolvent such as propane-2-ol, 1-butanol or DMSO in the presence of abase such as for example triethylamine,N-ethyl-N-(1-methylethyl)-2-propaneamine (DIPEA) and alike. Thecompounds according to the invention are finally obtained afterdeprotection and ring closure using art known conditions. Ring closureis typically performed in the presence of a coupling reagent such as forexample 1,3-dicyclohexylcarbodiimide (DCC), N,N′-carbonyldiimidazole(CDI), POCl₃, TiCl₄, sulfur chloride fluoride (SO₂ClF) or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) in the presence orabsence of hydroxybenzotrialzole (HOBt).

P₁ and P₂ each independently represent optionally protected functionalgroups, such as for example a primary or secondary amine, hydroxyl,hydroxycarbonyl, or halo (Cl, Br or I), which upon reaction producetogether with the Y₁ respectively Y₂ substituents to which they areattached, the divalent Y radical as defined for the compounds of formula(I) hereinbefore. X¹, X², R¹, R², R³ and R⁴ are defined as for thecompounds of formula (I) hereinbefore.

As further exemplified in the experimental part of the description, thegroup of compounds of formula (I) were —X¹— represents —O—, hereinafterreferred to as compounds of formula (I′), are generally prepared usingthe following synthesis scheme. The compounds of this invention may beprepared by coupling the known 4-chloro-6-chloropyrimidopyrimidine (II)with suitable substituted anilines (III), which in their turn can beprepared according to reaction schemes 3-7, furnish the intermediatecompounds (IV). Substitution under art known conditions of the 6-chlorogroup with an appropriate alkoxide, such as for example benzyloxide,methoxide, 2-trimethylsilylethanol, should give upon deprotection,respectively catalytic hydrogenation, TMSCl, Na₂S, TFA, the desiredMitsunobu precursor of formula (VI) (Scheme 1). Next, ring closure underMitsunobu conditions give the target compounds (I′).

V=hydrogen or a protective group such as for example, methylcarbonyl,t-butyl, methyl, ethyl, benzyl or trialkylsilyl groups; R representsbenzyl or methyl; and a¹-a²=a³-a⁴, Y, X², R¹, R², R³ and R⁴ are definedas for the compounds of formula (I)

Those compounds of formula (I′), where X² represents —O— and a¹-a²=a³-a⁴represents N—C═N—C are prepared by coupling the known8-chloro-2(methylthio)-pyrimido[5,4-d]pyrimidine (XXVII) with2-aminophenol derivatives of formula (XXVIII) yielding the intermediatecompounds of formula (XXIX). Next, after protection of the phenol andoxidation of the methylthio, the pyrimidopyrimidine of formula (VIII) isconverted into the intermediate of formula (IX) using the appropriatealkoxide. Subsequent deprotection followed by ring closure underMitsunobu conditions should give the target compounds of formula (I″).

V=hydrogen or a protective group such as for example, methylcarbonyl,t-butyl, methyl, ethyl, benzyl or trialkylsilyl groups; and Y, X², R¹,R², R³ and R⁴ are defined as for the compounds of formula (I)

Alternatively, those compounds of formula (I′), where X² represents —O—and a¹-a²=a³-a⁴ represents C—C═C—N, said compounds are prepared bycoupling the known 4-chloro-6-fluoropyridopyrimidines (II) with2-aminophenol derivatives of formula (XXVIII) yielding the intermediatecompounds of formula (VII). Next, after protection of the phenol, thepyridopyrimidine of formula (VIII) is converted into the intermediate offormula (IX) using the appropriate alkoxide. Subsequent deprotectionfollowed by ring closure under Mitsunobu conditions should give thetarget compounds of formula (I″).

V=hydrogen or a protective group such as for example, methylcarbonyl,t-butyl, methyl, ethyl, benzyl or trialkylsilyl groups; and Y, R¹, R²,R³ and R⁴ are defined as for the compounds of formula (I)

For those compounds where X² represents —O—, the suitable substitutedanilines of formula (III^(a)) are generally prepared from thecommercially available nitro-phenols (X) and the α, ω-protectedhalogenated alcohols (XI) under alkaline conditions in a reaction inertsolvent, for example, using dimethylacetamide (DMA) in the presence ofK₂CO₃. The resulting nitro-phenyl derivative (XII) is subsequentlyreduced according to standard conditions, for example, using iron/aceticacid, to yield the substituted anilines of formula (III^(a)) (Scheme 4).

-   -   X represents a halogen such as for example, Cl, Br and I    -   V represents a protective group such as for example        methylcarbonyl

For those compounds where X² represents —NR¹²— or —NR¹²—C₁₋₂alkyl-, thesuitable substituted anilines of formula (III^(b)) are generallyprepared from the commercially available 2-nitro-benzaldehydes (XIII)and the amine substituted alcohols (XIV) by reductive amination understandard conditions, for example using NaBH₄ and titanium(iv)isopropoxide as reducing agents in ethanol as solvent, yielding in afirst step the nitro-benzylamines of formula (XV).

Next the primary free alcohol is protected using art known procedures,for example, using an esterification reaction with acetic anhydride inthe presence of pyridine.

The thus obtained intermediate of formula (XVI) is subsequently reducedaccording to standard conditions, for example, using iron/acetic acid toyield the substituted anilines of formula (III^(b)) (Scheme 5).

-   -   V represents a protective group such as for example        methylcarbonyl    -   m=0 or 1 and n=1 or 2

For those compounds where X² represents —O—N═CH—, the suitablesubstituted anilines of formula (III^(c)) are generally preparedaccording to reaction scheme 5.

In a first step the known 2-nitro-benzaldehydes (XIII) are convertedinto the corresponding oxime (XVII) using, for example, the art knowncondensation reaction with hydroxylamine.

Next said oxime of formula XVII is allowed to react for example, with anhalogenated alkylacetate under alkaline conditions, for example usingK₂CO₃ in DMSO or with a stronger silyl protecting group like TBDMS orTBDPS, and NaH in THF for the reaction conditions, followed by reducingthe nitro group, for example, with iron/acetic acid, to provide thesuitable substituted aniline of formula (III^(c)).

-   -   X represents a halogen such as for example Cl, Br or I

For those compounds where X² represents a direct bond and Y representsC₁₋₆alkyl-NH—CO—, the suitable substituted anilines of formula (III^(d))are generally prepared according to reaction scheme 7.

In a first step the known 2-nitro-benzoic acids (XX) are amidated to theintermediates of formula (XXII) under art known conditions, for example,using a hydroxylated amine of formula (XXI) that is added dropwise to amixture of (XX) in CH₂Cl₂ in the presence of 1,1′carbonylbis-1H-imidazole.

Next the primary free alcohol is protected using art known procedures,for example, using an esterification reaction with acetic anhydride inthe presence of pyridine. The thus obtained intermediate of formula(XXIII) is subsequently reduced according to standard conditions, forexample, using iron/acetic acid to yield the substituted anilines offormula (III^(d)).

-   -   V represents a protective group such as for example        methylcarbonyl

For those compounds where X² represents a direct bond the suitablesubstituted anilines of formula (III^(c)) are generally preparedaccording to reaction scheme 7.

In a first step the known 2-nitro-benzaldehydes (XIII) are alkenated tothe intermediates of formula (XXV) under art known conditions, forexample, using the Wittig Reaction with the appropriate phosphonium saltof formula (XXIV).

Following esterification of the free carboxylic acid under standardconditions for example, using ethanol under acidic conditions, theintermediate of formula (XXVI) are reduced to yield the desiredsubstituted anilines of formula (III^(e)).

-   -   Y₁ represents a C₁₋₇alkyl

As further exemplified in the experimental part of the description, thegroup of compounds of formula (I) were —X¹— represents —NR¹¹— anda¹-a²=a³-a⁴ represents N—CH═N—CH, hereinafter referred to as compoundsof formula (I′″), are generally prepared using the following synthesisscheme (Scheme 9). Said compounds may be prepared by coupling the known8-chloro-2(methylthio)-pyrimido[5,4-d]pyrimidine with 2-aminophenolderivatives of formula (XXVIII), yielding the intermediate compounds offormula (XXIX).

Next, the pyrimido[5,4-d]pyrimidine of formula (XXIX) is aminated usingan aminated alcohol (XXX) under art known conditions, followed by ringclosure under Mitsunobu conditions to give the target compounds offormula (I′″).

Alternatively, for those compounds of formula (I) where —X¹— represents—NR¹¹— and a¹-a²=a³-a⁴ represents N—CH═CH—CH, the compounds are preparedby coupling the known 4,6-dichloro-(XXVII′) with 2-aminophenolderivatives of formula (XXVIII), yielding the intermediate compounds offormula (XXIX′).

Next, the pyrido[3,2-d]pyrimidine of formula (XXIX′) is aminated usingan aminated alcohol (XXX) under art known conditions, followed by ringclosure under Mitsunobo conditions to give the target compounds offormula (I″″) (Scheme 10).

Where necessary or desired, any one or more of the following furthersteps in any order may be performed:

-   (i) removing any remaining protecting group(s);-   (ii) converting a compound of formula (I) or a protected form    thereof into a further compound of formula (I) or a protected form    thereof;-   (iii) converting a compound of formula (I) or a protected form    thereof into a N-oxide, a salt, a quaternary amine or a solvate of a    compound of formula (I) or a protected form thereof;-   (iv) converting a N-oxide, a salt, a quaternary amine or a solvate    of a compound of formula (I) or a protected form thereof into a    compound of formula (I) or a protected form thereof;-   (v) converting a N-oxide, a salt, a quaternary amine or a solvate of    a compound of formula (I) or a protected form thereof into another    N-oxide, a pharmaceutically acceptable addition salt a quaternary    amine or a solvate of a compound of formula (I) or a protected form    thereof;-   (vi) where the compound of formula (I) is obtained as a mixture    of (R) and (S) enantiomers resolving the mixture to obtain the    desired enantiomer.

Compounds of formula (I), N-oxides, addition salts, quaternary aminesand stereochemical isomeric forms thereof can be converted into furthercompounds according to the invention using procedures known in the art.

It will be appreciated by those skilled in the art that in the processesdescribed above the functional groups of intermediate compounds may needto be blocked by protecting groups.

Functional groups, which it is desirable to protect, include hydroxy,amino and carboxylic acid. Suitable protecting groups for hydroxyinclude trialkylsilyl groups (e.g. tert-butyldimethylsilyl,tert-butyldiphenylsilyl or trimethylsilyl), benzyl andtetrahydropyranyl. Suitable protecting groups for amino includetert-butyloxycarbonyl or benzyloxycarbonyl. Suitable protecting groupsfor carboxylic acid include C₍₁₋₆₎alkyl or benzyl esters.

The protection and deprotection of functional groups may take placebefore or after a reaction step.

Additionally, the N-atoms in compounds of formula (I) can be methylatedby art-known methods using CH₃—I in a suitable solvent such as, forexample 2-propanone, tetrahydrofuran or dimethylformamide.

The compounds of formula (I) can also be converted into each otherfollowing art-known procedures of functional group transformation ofwhich some examples are mentioned hereinafter.

The compounds of formula (I) may also be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with3-phenyl-2-(phenylsulfonyl)oxaziridine or with an appropriate organic orinorganic peroxide. Appropriate inorganic peroxides comprise, forexample, hydrogen peroxide, alkali metal or earth alkaline metalperoxides, e.g. sodium peroxide, potassium peroxide; appropriate organicperoxides may comprise peroxy acids such as, for example,benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid,e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g.peroxoacetic acid, alkylhydroperoxides, e.g. t-butyl hydroperoxide.Suitable solvents are, for example, water, lower alkanols, e.g. ethanoland the like, hydro-carbons, e.g. toluene, ketones, e.g. 2-butanone,halogenated hydrocarbons, e.g. dichloromethane, and mixtures of suchsolvents.

Pure stereochemically isomeric forms of the compounds of formula (I) maybe obtained by the application of art-known procedures. Diastereomersmay be separated by physical methods such as selective crystallizationand chromatographic techniques, e.g. counter-current distribution,liquid chromatography and the like.

Some of the compounds of formula (I) and some of the intermediates inthe present invention may contain an asymmetric carbon atom. Purestereochemically isomeric forms of said compounds and said intermediatescan be obtained by the application of art-known procedures. For example,diastereoisomers can be separated by physical methods such as selectivecrystallization or chromatographic techniques, e.g. counter currentdistribution, liquid chromatography and the like methods. Enantiomerscan be obtained from racemic mixtures by first converting said racemicmixtures with suitable resolving agents such as, for example, chiralacids, to mixtures of diastereomeric salts or compounds; then physicallyseparating said mixtures of diastereomeric salts or compounds by, forexample, selective crystallization or chromatographic techniques, e.g.liquid chromatography and the like methods; and finally converting saidseparated diastereomeric salts or compounds into the correspondingenantiomers. Pure stereochemically isomeric forms may also be obtainedfrom the pure stereochemically isomeric forms of the appropriateintermediates and starting materials, provided that the interveningreactions occur stereospecifically.

An alternative manner of separating the enantiomeric forms of thecompounds of formula (I) and intermediates involves liquidchromatography, in particular liquid chromatography using a chiralstationary phase.

Some of the intermediates and starting materials as used in the reactionprocedures mentioned hereinabove are known compounds and may becommercially available or may be prepared according to art-knownprocedures. However, in the synthesis of the compounds of formula (I),the present invention further provides the intermediates of formula(III)

the pharmaceutically acceptable addition salts and the stereochemicallyisomeric forms thereof, wherein

-   V represents hydrogen or a protective group preferably selected from    the group consisting of methylcarbonyl, t-butyl, methyl, ethyl,    benzyl or trialkylsilyl;

Y represents —C₃₋₉alkyl-, —C₃₋₉alkenyl-, —C₁₋₅alkyl-oxy-C₁₋₅alkyl-,—C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-, —C₁₋₅alkyl-NR¹⁴—CO—C₁₋₅alkyl-,—C₁₋₅alkyl-CO—NR¹⁵—C₁₋₅alkyl-, —C₁₋₆alkyl-CO—NH—, —C₁₋₆alkyl-NH—CO—,—C₁₋₇alkyl-CO—, C₁₋₆alkyl-CO—C₁₋₆alkyl;

-   X² represents a direct bond, O, —O—C₁₋₂alkyl-, CO, —CO—C₁₋₂alkyl-,    NR¹², —NR¹²—C₁₋₂alkyl-, —CH₂—, —O—N═CH— or C₁₋₂alkyl;-   R¹ represents hydrogen, cyano, halo, hydroxy, formyl, C₁₋₆alkoxy-,    C₁₋₆alkyl-, C₁₋₆alkoxy- substituted with halo,    -   C₁₋₄alkyl substituted with one or where possible two or more        substituents selected from hydroxy or halo; and-   R² represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-,    Het¹⁶-carbonyl-, C₁₋₄alkyloxycarbonyl-, C₁₋₄alkylcarbonyl-,    aminocarbonyl-, mono- or di(C₁₋₄alkyeaminocarbonyl-, Het¹, formyl,    C₁₋₄alkyl-, C₂₋₆alkynyl-, C₃₋₆cycloalkyl-, C₃₋₆cycloalkyloxy-,    C₁₋₆alkoxy-, Ar⁵, Ar¹-oxy-, dihydroxyborane, C₁₋₆alkoxy- substituted    with halo,    -   C₁₋₄alkyl substituted with one or where possible two or more        substituents selected from halo, hydroxy or NR⁵R⁶,    -   C₁₋₄alkylcarbonyl- wherein said C₁₋₄alkyl is optionally        substituted with one or where possible two or more substituents        selected from hydroxy or C₁₋₄alkyl-oxy-;-   R⁵ and R⁶ are each independently selected from hydrogen or    C₁₋₄alkyl;-   R¹² represents hydrogen, C₁₋₄alkyl, C₁₋₄alkyl-oxy-carbonyl-, Het¹⁷,    Het¹⁸-C₁₋₄alkyl-, C₂₋₄alkenylcarbonyl- optionally substituted with    Het¹⁹-C₁₋₄alkylaminocarbonyl-, C₂₋₄alkenylsulfonyl-,    C₁₋₄alkyloxyC₁₋₄alkyl- or phenyl optionally substituted with one or    where possible two or more substituents selected from hydrogen,    hydroxy, amino or C₁₋₄alkyloxy-;-   R¹³ represents hydrogen, C₁₋₄alkyl, Het¹³, Het¹⁴-C₁₋₄alkyl- or    phenyl optionally substituted with one or where possible two or more    substituents selected from hydrogen, hydroxy, amino or    C₁₋₄alkyloxy-;-   R¹⁴ and R¹⁵ are each independently selected from hydrogen,    C₁₋₄alkyl, Het¹⁵-C₁₋₄alkyl- or C₁₋₄alkyloxyC₁₋₄alkyl-;-   Het¹ represents a heterocycle selected from piperidinyl,    morpholinyl, piperazinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl,    oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or    pyrrolidinyl wherein said Het¹ is optionally substituted amino,    C₁₋₄alkyl, hydroxy-C₁₋₄alkyl-, phenyl, phenyl-C₁₋₄alkyl-,    C₁₋₄alkyl-oxy-C₁₋₄alkyl- mono- or di(C₁₋₄alkyl)amino- or    amino-carbonyl-;-   Het¹³ represent a heterocycle selected from pyrrolidinyl or    piperidinyl wherein said heterocycle is optionally substituted with    one or where possible two or more substituents selected from    C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄allyl-, C₁₋₄alkyloxyC₁₋₄alkyl    or polyhydroxy-C₁₋₄alkyl-;-   Het¹⁴ represent a heterocycle selected from morpholinyl,    pyrrolidinyl, piperazinyl or piperidinyl wherein said heterocycle is    optionally substituted with one or where possible two or more    substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl,    hydroxy-C₁₋₄allyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-;-   Het¹⁵ represent a heterocycle selected from morpholinyl,    pyrrolidinyl, piperazinyl or piperidinyl wherein said heterocycle is    optionally substituted with one or where possible two or more    substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl,    hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-;-   Het¹⁶ represent a heterocycle selected from morpholinyl,    pyrrolidinyl, piperazinyl, 1,3,2-dioxaborolane or piperidinyl    wherein said heterocycle is optionally substituted with one or more    substituents selected from C₁₋₄alkyl; and-   Het¹⁷ represent a heterocycle selected from pyrrolidinyl or    piperidinyl wherein said heterocycle is optionally substituted with    one or where possible two or more substituents selected from    C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl    or polyhydroxy-C₁₋₄alkyl-;-   Het¹⁸ and Het¹⁹ each independently represent a heterocycle selected    from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl wherein    said Het¹⁸ and Het¹⁹ are optionally substituted with one or where    possible two or more substituents selected from C₁₋₄alkyl,    C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or    polyhydroxy-C₁₋₄alkyl-;-   Ar¹, Ar², Ar³, Ar⁴ and Ar⁵ each independently represent phenyl    optionally substituted with cyano, C₁₋₄alkylsulfonyl-,    C₁₋₄alkylsulfonylamino-, aminosulfonylamino-, hydroxy-C₁₋₄alkyl,    aminosulfonyl-, hydroxy-, C₁₋₄alkyloxy- or C₁₋₄alkyl.

In particular the intermediates of formula (III) wherein one or more ofthe following restrictions apply;

-   i) Y represents —C₃₋₉ alkyl-, —C₁₋₅alkyl-oxy-C₁₋₅alkyl-,    —C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-, —C₁₋₆alkyl-NH—CO—;-   ii) X² represents a direct bond, O, —O—C₁₋₂alkyl-, NR¹²,    —NR¹²—C₁₋₂alkyl-, —CH₂—, —O—N═CH— or C₁₋₂alkyl;-   iii) R¹ represents hydrogen, cyano, halo or hydroxy, preferably    halo;-   iv) R² represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-,    C₁₋₄alkyloxycarbonyl-, Het¹⁶-carbonyl-, C₁₋₄alkyl-, C₂₋₆alkynyl-,    Ar⁵ or Het¹;    -   In a further embodiment R² represents hydrogen, cyano, halo,        hydroxy, C₂₋₆alkynyl- or Het¹; in particular R² represents        hydrogen, cyano, halo, hydroxy, or Ar⁵;-   v) R¹² represents hydrogen, C₁₋₄alkyl, or C₁₋₄alkyloxycarbonyl;-   vi) R¹³ represents Het¹⁴-C₁₋₄alkyl, in particular    morpholinyl-C₁₋₄alkyl;-   vii) Het¹ represents thiazolyl optionally substituted with amino,    C₁₋₄alkyl, hydroxy-C₁₋₄alkyl-, phenyl, phenyl-C₁₋₄alkyl-,    C₁₋₄alkyl-oxy-C₁₋₄alkyl-, mono- or di(C₁₋₄alkyl)amino- or    amino-carbonyl-;-   viii) Het¹⁶ represents a heterocycle selected from piperidinyl or    pyrrolidinyl.-   It is also an object of the present invention to provide the use of    an intermediate of formula (III) in the synthesis of a macrocyclic    kinase inhibitor such as for example compound of formula (I).

The compounds of formula (I) and the intermediates of formula (XXXI) ofthe present invention are useful because they possess pharmacologicalproperties. They can therefore be used as medicines.

Accordingly, in a further aspect this invention concerns theintermediates of formula (XXXI)

-   the N-oxide forms, the pharmaceutically acceptable addition salts    and the stereochemically isomeric forms thereof, wherein-   a¹-a²=a³-a⁴ represents a divalent radical selected from N—CH═CH—CH    or N—CH═N—CH;-   Y represents —C₃₋₉alkyl-, —C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-,    —C₁₋₆alkyl-NH—CO— or —CO—NH—C₁₋₆alkyl-;-   R¹ represents hydrogen or halo;-   R² represents hydrogen, cyano, halo, hydroxycarbonyl-,    C₁₋₄alkyloxycarbonyl-, Het¹⁶-carbonyl- or Ar⁵;-   R⁴ represents hydroxy, C₁₋₄alkyloxy-, Ar⁴—C₁₋₄alkyloxy or R⁴    represents C₁₋₄alkyloxy substituted with one or where possible two    or more substituents selected from C₁₋₄alkyloxy- or Het²-;-   R¹¹ represents hydrogen;-   R¹³ represents Het¹⁴-C₁₋₄alkyl, in particular morpholinyl-C₁₋₄alkyl;-   Het² represents a heterocycle selected from morpholinyl,    piperazinyl, piperidinyl or pyrrolidinyl wherein said Het² is    optionally substituted with one or where possible two or more    substituents selected from hydroxy, amino or C₁₋₄alkyl-;    -   In a further embodiment Het² represents a heterocycle selected        from morpholinyl or piperidinyl optionally substituted with        C₁₋₄alkyl-, preferably methyl;-   Het¹⁴ represents morpholinyl;-   Het¹⁶ represents a heterocycle selected from morpholinyl or    pyrrolidinyl;-   Ar⁴ represents phenyl;-   Ar⁵ represents phenyl optionally substituted with cyano; as well as    the use of an intermediate of formula (XXXI) in the synthesis of a    macrocyclic kinase inhibitor such as for example the compounds of    formula (I).

As described in the experimental part hereinafter, the growth inhibitoryeffect and anti-tumour activity of the present compounds and some of theintermediates has been demonstrated in vitro, in enzymatic assays on thereceptor tyrosine kinase EGFR. In an alternative assay, the growthinhibitory effect of the compounds was tested on the ovarian carcinomacell line SKOV3 using art known cytotoxicity assays such as LIVE/DEAD(Molecular Probes) or MTT.

Accordingly, the present invention provides the compounds of formula (I)and the intermediates of formula (XXXI) and their pharmaceuticallyacceptable N-oxides, addition salts, quaternary amines andstereochemically isomeric forms for use in therapy. More particular inthe treatment or prevention of cell proliferation mediated diseases. Thecompounds of formula (I), the intermediates of formula (XXXI) and theirpharmaceutically acceptable N-oxides, addition salts, quaternary aminesand the stereochemically isomeric forms may hereinafter be referred toas compounds according to the invention.

Disorders for which the compounds according to the invention areparticularly useful are atherosclerosis, restenosis, cancer and diabeticcomplications e.g. retinopathy. In view of the utility of the compoundsaccording to the invention, there is provided a method of treating acell proliferative disorder such as atherosclerosis, restenosis andcancer, the method comprising administering to an animal in need of suchtreatment, for example, a mammal including humans, suffering from a cellproliferative disorder, a therapeutically effective amount of a compoundaccording to the present invention.

Said method comprising the systemic or topical administration of aneffective amount of a compound according to the invention, to animals,including humans. One skilled in the art will recognize that atherapeutically effective amount of the EGFR inhibitors of the presentinvention is the amount sufficient to induce the growth inhibitoryeffect and that this amount varies inter alia, depending on the size,the type of the neoplasia, the concentration of the compound in thetherapeutic formulation, and the condition of the patient. Generally, anamount of EGFR inhibitor to be administered as a therapeutic agent fortreating cell proliferative disorder such as atherosclerosis, restenosisand cancer, will be determined on a case by case by an attendingphysician.

Generally, a suitable dose is one that results in a concentration of theEGFR inhibitor at the treatment site in the range of 0.5 nM to 200 μM,and more usually 5 nM to 10 μM. To obtain these treatmentconcentrations, a patient in need of treatment likely will beadministered between 0.01 mg/kg to 300 mg/kg body weight, in particularfrom 10 mg/kg to 100 mg/kg body weight. As noted above, the aboveamounts may vary on a case-by-case basis. In these methods of treatmentthe compounds according to the invention are preferably formulated priorto admission. As described herein below, suitable pharmaceuticalformulations are prepared by known procedures using well known andreadily available ingredients.

Due to their high degree of selectivity as EGFR inhibitors, thecompounds of formula (I) and the intermediates of formula (XXXI) asdefined above, are also useful to mark or identify the kinase domainwithin the receptor tyrosine kinase receptors. To this purpose, thecompounds of the present invention can be labelled, in particular byreplacing, partially or completely, one or more atoms in the molecule bytheir radioactive isotopes. Examples of interesting labelled compoundsare those compounds having at least one halo which is a radioactiveisotope of iodine, bromine or fluorine; or those compounds having atleast one ¹¹C-atom or tritium atom.

One particular group consists of those compounds of formula (I) andintermediates of formula (XXXI) wherein R¹ is a radioactive halogenatom. In principle, any compound according to the invention containing ahalogen atom is prone for radiolabelling by replacing the halogen atomby a suitable isotope. Suitable halogen radioisotopes to this purposeare radioactive iodides, e.g. ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I; radioactivebromides, e.g. ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br, and radioactive fluorides,e.g. ¹⁸F. The introduction of a radioactive halogen atom can beperformed by a suitable exchange reaction or by using any one of theprocedures as described hereinabove to prepare halogen derivatives offormula (I).

Another interesting form of radiolabelling is by substituting a carbonatom by a ¹¹C-atom or the substitution of a hydrogen atom by a tritiumatom.

Hence, said radiolabelled compounds according to the invention can beused in a process of specifically marking receptor sites in biologicalmaterial. Said process comprises the steps of (a) radiolabelling acompound according to the invention, (b) administering thisradiolabelled compound to biological material and subsequently (c)detecting the emissions from the radiolabelled compound.

The term biological material is meant to comprise every kind of materialwhich has a biological origin. More in particular this term refers totissue samples, plasma or body fluids but also to animals, speciallywarm-blooded animals, or parts of animals such as organs.

When used in in vivo assays, the radiolabelled compounds areadministered in an appropriate composition to an animal and the locationof said radiolabelled compounds is detected using imaging techniques,such as, for instance, Single Photon Emission Computerized Tomography(SPECT) or Positron Emission Tomography (PET) and the like. In thismanner the distribution of the particular receptor sites throughout thebody can be detected and organs containing said receptor sites can bevisualized by the imaging techniques mentioned hereinabove. This processof imaging an organ by administering a radiolabelled compound of formula(I) and detecting the emissions from the radioactive compound alsoconstitutes a part of the present invention.

In yet a further aspect, the present invention provides the use of thecompounds according to the invention in the manufacture of a medicamentfor treating any of the aforementioned cell proliferative disorders orindications.

The amount of a compound according to the present invention, alsoreferred to here as the active ingredient, which is required to achievea therapeutical effect will be, of course, vary with the particularcompound, the route of administration, the age and condition of therecipient, and the particular disorder or disease being treated. Asuitable daily dose would be from 0.01 mg/kg to 300 mg/kg body weight,in particular from 10 mg/kg to 100 mg/kg body weight. A method oftreatment may also include administering the active ingredient on aregimen of between one and four intakes per day.

While it is possible for the active ingredient to be administered alone,it is preferable to present it as a pharmaceutical composition.Accordingly, the present invention further provides a pharmaceuticalcomposition comprising a compound according to the present invention,together with a pharmaceutically acceptable carrier or diluent. Thecarrier or diluent must be “acceptable” in the sense of being compatiblewith the other ingredients of the composition and not deleterious to therecipients thereof.

The pharmaceutical compositions of this invention may be prepared by anymethods well known in the art of pharmacy, for example, using methodssuch as those described in Gennaro et al. Remington's PharmaceuticalSciences (18^(th) ed., Mack Publishing Company, 1990, see especiallyPart 8: Pharmaceutical preparations and their Manufacture). Atherapeutically effective amount of the particular compound, in baseform or addition salt form, as the active ingredient is combined inintimate admixture with a pharmaceutically acceptable carrier, which maytake a wide variety of forms depending on the form of preparationdesired for administration. These pharmaceutical compositions aredesirably in unitary dosage form suitable, preferably, for systemicadministration such as oral, percutaneous or parenteral administration;or topical administration such as via inhalation, a nose spray, eyedrops or via a cream, gel, shampoo or the like. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed, such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs and solutions: orsolid carriers such as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets. Because of their ease in administration, tabletsand capsules represent the most advantageous oral dosage unit form, inwhich case solid pharmaceutical carriers are obviously employed. Forparenteral compositions, the carrier will usually comprise sterilewater, at least in large part, though other ingredients, for example, toaid solubility, may be included. Injectable solutions, for example, maybe prepared in which the carrier comprises saline solution, glucosesolution or a mixture of saline and glucose solution. Injectablesuspensions may also be prepared in which case appropriate liquidcarriers, suspending agents and the like may be employed. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewettable agent, optionally combined with suitable additives of anynature in minor proportions, which additives do not cause anysignificant deleterious effects on the skin. Said additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as a spot-onor as an ointment.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

EXPERIMENTAL PART

Hereinafter, the term ‘ADDP’ means 1,1′-(azodicarbonyl)bis-piperidine,‘DMF’ means N,N-dimethylformamide, ‘THF’ means tetrahydrofuran, “DMSO”means dimethyl sulfoxide

A. Preparation of the Intermediates Example A1 a) Preparation of phenol,4-chloro-2-[(6-chloropyrido[3,2-d]pyrimidin-4-yl)amino]- (Intermediate1)

A mixture of 4,6-dichloro-pyrido[3,2-d]pyrimidine (0.00255 mol) and4-chloro-2-aminophenol (0.00446 mol) in isopropanol (30 ml) was stirredat 50° C. for 2 h30, then brought to room temperature and evaporated todryness. The residue was taken up in ether, filtered and dried, yielding1 g (100%) of intermediate 1.

b) Preparation of phenol,4-chloro-2-[[6-[(6-hydroxyhexyl)amino]pyrido[3,2-d]pyrimidin-4-yl]amino]-(Intermediate 2)

A mixture of intermediate 1 (0.00255 mol) and 6-amino-1-hexanol (0.0255mol) was stirred at 100° C. for 3 hours, then brought to roomtemperature. The residue was purified by chromatography over silica gel(eluent: DCM/MeOH/NH₄OH 97/3/0.1; 70-200 μm), yielding 0.71 g (72%) ofintermediate 2, melting point 260° C.

Example A2 Preparation of phenol,4-chloro-2-[[6-[(4-hydroxybutyl)amino]pyrido[3,2-d]pyrimidin-4-yl]amino]-(Intermediate 3)

A mixture of intermediate 1 (0.0013 mol) and 4-amino-1-butanol (0.026mol) was stirred at 100° C. for 4 hours, then brought to roomtemperature and hydrolyzed a saturated solution of sodium chloride. Themixture was extracted by DCM, decanted, dried over MgSO₄, filtered, andthe solvent was evaporated till dryness. The residue (0.5 g) waspurified by column chromatography over silica gel (eluent:DCM/MeOH/NH₄OH95/5/0.1; 70-200 μm). The residue (81 mg, 17%) was crystallized fromacetonitrile and diethyl ether. The precipitate was filtered off anddried, yielding 69 mg (15%) of intermediate 3, melting point 227° C.

Example A3 Preparation of phenol,4-chloro-2-[[6-[(5-hydroxypentyl)amino]pyrido[3,2-d]pyrimidin-4-yl]amino]-(Intermediate 4)

A mixture of intermediate 1 (0.0013 mol) and 5-amino-1-pentanol (0.0195mol) was stirred at 100° C. for 4 hours, then brought to roomtemperature and hydrolyzed a saturated of sodium chloride. The mixturewas extracted by DCM, decanted and dried over MgSO₄, filtered, and thesolvent was evaporated till dryness. The residue (0.45 g) was purifiedby column chromatography over silica gel (eluent: DCM/MeOH/NH₄OH95/5/0.1; 70-200 μm). The residue (66 mg, 14%) was crystallized fromacetonitrile and diethyl ether. The precipitate was filtered off anddried, yielding 59 mg (12%) of intermediate 4, melting point 240° C.

Example A4 a) Preparation of phenol,4-chloro-2-[[6-(methylthio)pyrimido[5,4-d]pyrimidin-4-yl]amino]-(Intermediate 5)

A mixture of 8-chloro-2-(methylthio)-pyrimido[5,4-d]pyrimidine (0.0047mol) and 2-amino-4-chlorophenol (0.0094 mol) in dioxane (5 ml) wasstirred at 80° C. for 1 hour, then cooled to room temperature, theprecipitate was filtered off, washed with water and then with diethylether and dried in vacuo, yielding 1.2 g (80%) of intermediate 5.

b) Preparation of phenol,4-chloro-2-[[6-[(6-hydroxyhexyl)amino]pyrimido[5,4-d]pyrimidin-4-yl]amino]-(Intermediate 6)

A mixture of intermediate 1 (0.00172 mol) in 6-amino-1-hexanol (0.0022mol) was melt at 100° C. after 8 hours. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH97/3/0.1; 35-70 μm) yielding 0.170 g of solid. Ether was added. Thesolid was filtered off and dried in vacuo, yielding 135 mg (20%) ofintermediate (6).

Example A5 a) Preparation of pyrido[3,2-d]pyrimidine, 4,6-dichloro-(Intermediate 7)

DMF (3 drops) was added to a mixture of6-chloro-pyrido[3,2-d]pyrimidin-4(1H)-one

[171178-33-9] (0.00275 mol) and thionyl chloride (0.179 mol). Thereaction mixture was stirred and refluxed (at 80° C.) for 90 minutes.The solvent was evaporated. Some dichloromethane was added and thesolvent was evaporated. The residue was dissolved in dichloromethane.The organic solution was washed with a saturated aqueous K₂CO₃ solution,then dried (MgSO₄), filtered and the solvent was evaporated, yielding0.49 g (89%) of intermediate (7). (HPLC: 85% P).

b) Preparation of4-[2-(6-Chloro-pyrido[3,2-d]pyrimidin-4-ylamino)-phenoxy]-butyric acidethyl ester (Intermediate 8)

Intermediate (7) (0.00245 mol) was dissolved in 2-propanol (20 ml) (notvery soluble).

4-(2-Aminophenoxy)butanoic acid ethyl ester (0.00416 mol) was added,followed by addition of N,N-diethylethanamine (0.00490 mol). Thereaction mixture was stirred and refluxed overnight. Then, the reactionmixture was cooled to room temperature and the solvent was evaporated.The residue was taken up into diethyl ether. The precipitate wasfiltered off and dried (pump), yielding 1.48 g of fraction (1) (greenishsolid, 92% P by HPLC-MS; presence of some starting material B). Thisfraction (1) was purified as described below.

The reaction was repeated.

Intermediate (7) (0.0055 mol) was dissolved in 2-propanol (40 ml) (notvery soluble). 4-(2-Aminophenoxy)butanoic acid, ethyl ester (0.00935mol) was added, followed by addition of N,N-diethylethanamine (0.0110mol). The reaction mixture was stirred and refluxed overnight. Then, thereaction mixture was cooled to room temperature and the solvent wasevaporated. The residue was combined with fraction (1) and subjected toflash column chromatography over silica gel (eluent: n-hexane/EtOAc3/1). The product fractions were collected and the solvent wasevaporated, yielding 3.04 g of intermediate (8)(greenish solid inquantitative yield, used in next reaction step without furtherpurification).

c) Preparation of4-{2-[6-(3-tert-Butoxycarbonylamino-propylamino)-pyrido[3,2-d]pyrimidin-4-ylamino]-phenoxy}-butyricacid ethyl ester (Intermediate 9)

Intermediate (8) (0.00026 mol) and (3-aminopropyl)carbamic acid1,1-dimethylethyl ester (0.00288 mol) were mixed for 3 hours at 100° C.in a closed reactor, yielding fraction (1) (57% P by HPLC+35% of theamide).

This fraction (1) was purified as described below.

The reaction was repeated.

Intermediate (8) (0.00026 mol) and (3-aminopropyl)carbamic acid1,1-dimethylethyl ester (0.00288 mol) were mixed for 2.5 hours at 100°C. in an open reaction flask (not in a closed reactor as describedabove). The mixture was combined with fraction (1). Purified by flashcolumn chromatography over silica gel (eluent:n-hexane/EtOAc 3/1). Theproduct fractions were collected and the solvent was evaporated,yielding intermediate (9) (HPLC: 92% P).

d) Preparation of4-{2-[6-(3-Amino-propylamino)-pyrido[3,2-d]pyrimidin-4-ylamino]-phenoxy}-butyricacid ethyl ester (Intermediate 10)

Intermediate (9) ((0.00019 mol) was dissolved in dichloromethane (4.00ml). Trifluoroacetic acid (0.05192 mol) was added and the reactionmixture was stirred for 2 hours at room temperature. The solvent andremaining acid were evaporated in the rotary evaporator. The resultantresidue (oil) was dried (high-vacuum pump), yielding intermediate (10)(HPLC: 93% P; quantitative yield; used in next reaction step, withoutfurther purification).

e) Preparation of4-{2-[6-(3-Amino-propylamino)-pyrido[3,2-d]pyrimidin-4-ylamino]-phenoxy}-butyricacid (Intermediate 11)

Intermediate (10) (0.00019 mol; 1 equiv) was dissolved intetrahydrofuran (8.00 ml).

Water (1.00 ml) was added. Lithium hydroxide monohydrate (0.0019 mol)was added as a solid. More Lithium hydroxide monohydrate was added untila basic pH was reached (until then it was acidic because of CF₃COOHremainders). The reaction mixture was stirred for 2 days at 65° C. Thesolvent was evaporated in the rotary evaporator, yielding intermediate(11). (HPLC: 78% P; quantitative yield; used in next reaction step,without further purification).

Example A6 a) Preparation of 4-chloro-6-fluoro-pyrido[3,4-d]pyrimidine,(Intermediate 12)

DMF (5 drops) was added to a mixture of6-Fluoro-3H-pyrido[3,4-d]pyrimidin-4-one (0.00605 mol) and thionylchloride (0.39 mol). The reaction mixture was stirred and refluxed (at80° C.) for 7 hours. The solvent was evaporated, yielding 1.254 g ofintermediate (12) (impure quantitative yield; used in next reactionstep, without further purification).

b) Preparation of4-[2-(6-Fluoro-pyrido[3,4-d]pyrimidin-4-ylamino)-phenoxy]-butyric acidethyl ester (Intermediate 13)

Intermediate (12) (0.00605 mol) was dissolved in 2-propanol (40 ml).4-(2-aminophenoxy)-butanoic acid, ethyl ester[112290-16-1].hydrochloride (0.01028 mol) was added, followed byaddition of N,N-diethylethanamine (0.01210 mol). The reaction mixturewas stirred and refluxed overnight. Then, the reaction mixture wascooled to room temperature and the solvent was evaporated. The residuewas purified by flash column chromatography over silica gel(eluent:n-hexane/EtOAc 3/1). The product fractions were collected andthe solvent was evaporated, yielding 0.922 g of intermediate (13) (41%yield over two steps; yellowish solid; 97% P by HPLC).

c) Preparation of4-{2-[6-(3-tert-Butoxycarbonylamino-propylamino)-pyrido[3,4-d]pyrimidin-4-ylamino]-phenoxy}-butyricacid ethyl ester (Intermediate 14)

Intermediate (13) (0.00027 mol) was dissolved in DMSO (q.s.), in areactor. (3-Aminopropyl)carbamic acid 1,1-dimethylethyl ester[75178-96-0] (0.07 ml) and N-ethyl-N-(1-methylethyl)-2-propanamine[7087-68-5] (0.10 ml) were added. The reactor was closed and the mixturewas heated for 7 days at 80° C. The reaction mixture was poured out intowater and the product was extracted three times with dichloromethane.The combined organic layers were dried (MgSO₄), filtered and the solventwas evaporated, yielding fraction 1 of intermediate (14).

Two other fractions of Intermediate 14 were prepared as follows:

Intermediate (13) (0.00027 mol) and (3-aminopropyl)carbamic acid1,1-dimethylethyl ester [75178-96-0] (0.00299 mol) were mixed in a(closed) reactor and heated at 100° C. for 3 hours, yielding fraction 2of intermediate (14).

Intermediate (13) (0.00008 mol) and (3-aminopropyl)carbamic acid1,1-dimethylethyl ester [75178-96-0] (0.0009 mol) were mixed in an openreaction flask and heated at 80° C. for 3 days, yielding fraction 3 ofintermediate (14)

Fraction 1, 2 and 3 of intermediate 14 were combined and purified byflash column chromatography over silica gel.

Intermediate 14 was also prepared as follows:

Intermediate (13) (0.00027 mol) was dissolved in DMF (3 ml).(3-Aminopropyl)carbamic acid 1,1-dimethylethyl ester [75178-96-0](0.00040 mol) and cesium carbonate (0.00135 mol) were added and thereaction mixture was stirred for 4 hours at 100° C., then overnight at115° C. Excess of cesium carbonate was removed by filtration. Thefiltrate was evaporated, yielding intermediate (14).

d) Preparation of4-{2-[6-(3-Amino-propylamino)-pyrido[3,4-d]pyrimidin-4-ylamino]-phenoxy}-butyricacid ethyl ester (Intermediate 15)

Intermediate (14) (0.00055 mol) was dissolved in dichloromethane (11.00ml). Trifluoroacetic acid (0.143 mol) was added and the reaction mixturewas stirred for 2 hours at room temperature. The solvent and remainingacid were evaporated in the rotary evaporator. The resultant residue(oil) was dried (high-vacuum pump), yielding intermediate (15) (HPLC:91% P; quantitative yield; used in next reaction step, without furtherpurification).

e) Preparation of4-{2-[6-(3-Amino-propylamino)-pyrido[3,4-d]pyrimidin-4-ylamino]-phenoxy}-butyricacid (Intermediate 16)

Intermediate (15) (0.00055 mol) was dissolved in tetrahydrofuran (16.00ml). Water (2.00 ml) was added. Lithium hydroxide.monohydrate (0.0055mol) was added as a solid. More lithium hydroxide.monohydrate was addeduntil a basic pH was reached (until then it was acidic because ofCF₃COOH remainders). The reaction mixture was stirred overnight at 65°C. The solvent was evaporated in the rotary evaporator, yieldingintermediate (16) (HPLC: 88% P; quantitative yield; used in nextreaction step, without further purification).

Example A7 a) Preparation ofAllyl-(4-chloro-5-fluoro-2-nitro-benzyl)-methyl-amine (Intermediate 17)

N-methyl-2-propen-1-amine (1.1 equiv) was added to a solution of4-chloro-5-fluoro-2-nitro-benzaldehyde (1 equiv) in 1,2-dichloroethane(207 ml), then MgSO₄ (2 spoons) was added and the obtained solution wasstirred for 2 hours at room temperature. NaBH(OAc)₃ (3 equiv) was addedin 5 portions (one portion per hour) and the reaction mixture was washedwith K₂CO₃. After extraction with CH₂Cl₂, the layers were separated. Theorganic layer was dried over MgSO₄, filtered and evaporated, to affordintermediate (17).

b) Preparation of2-[(Allyl-methyl-amino)-methyl]-5-chloro-4-fluoro-phenylamine(Intermediate 18)

A solution of the nitro derivative intermediate (17) (1 equiv) in asolution of H₂O (120 ml) and NH₄Cl (5 equiv) at room temperature wasdissolved in Toluene (120 ml), then iron powder (5 equiv) was slowlyadded and the reaction mixture was stirred and refluxed at 105° C. Theobtained crude was purified by Flash Chromatography. The desired productfractions were collected and the solvent was evaporated, to afford 4.8 gof intermediate (18).

c) Preparation of{2-[(Allyl-methyl-amino)-methyl]-5-chloro-4-fluoro-phenyl}-(6-chloro-pyrido[3,2-d]pyrimidin-4-yl)-amine(Intermediate 19)

Triethylamine (3 equiv) was added to a solution of4,6-dichloro-pyrido[3,2-d]pyrimidine (1 equiv.) in acetonitrile (driedover Al₂CO₃) (9 ml). HCl evolved and the reaction mixture was purgedwith N₂ for 10 to 15 minutes. Intermediate (18) was added (1.7 equiv.)and then the reaction mixture was stirred and refluxed for 5 hours.After cooling to room temperature, a slightly yellow solid precipitatedfrom the mixture. The product was collected and dried under high vacuum,to yield desired product. EtOAc was added to the mother layer and then awhite solid precipitated. After filtration, the filtrate wasconcentrated and the obtained concentrate was purified by Flashchromatography over silica gel (eluent: Hexane/EtOAc 9/1). The desiredfractions were collected and the solvent was evaporated, to yielddesired product. Both fractions of desired product were collected, toyield 0.750 g intermediate (19).

d) Preparation ofN⁶-Allyl-N⁴-{2-[(allyl-methyl-amino)-methyl]-5-chloro-4-fluoro-phenyl}-pyrido[3,2-d]pyrimidine-4,6-diamine(Intermediate 20)

A solution of intermediate (19) (1 equiv) in 2-propenylamine (9.8 equiv)was heated overnight in a sealed tube at 100° C., then the resultingsolution was concentrated and dried under high vacuum, to obtain 0.487 g(115%) of a semi solid that was redissolved in CH₂Cl2₂. The solution wasthen filtered and the filtrate was concentrated again, to afford 0.412 g(100%) of intermediate (20).

e) Preparation of4,6-ethanediylidenepyrimido[4,5-b][1,4,6,11]benzotetraazacyclotetradecine,16-chloro-15-fluoro-7,8,11,12,13,18-hexahydro-12-methyl-, (9E)-(Intermediate 21)

A mixture of intermediate (20) and Grubbs's Catalyst second generation(0.2 equiv) in CH₂Cl₂ (7 ml) was stirred and refluxed for 6 hours, thenthe reaction mixture was stirred for 72 hours at room temperature andrefluxed again. An extra amount of B (20%) was added and then theresulting mixture was stirred and refluxed again for 6 hours. Againextra B (20%) was added and the mixture was refluxed again overnight.After concentration, the obtained residue was purified by Flashchromatography over silica gel (eluent: Acetate/Hexane 1/1). The desiredfraction were collected and the solvent was evaporated, to yield 0.025 g(38%) of pure intermediate (21).

B. Preparation of the compounds Example B1 Preparation of7H,19H-4,6-ethanediylidenepyrimido[4,5-b][13,1,4,6]benzoxatriazacyclopentadecine,17-chloro-8,9,10,11,12,13-hexahydro- (Compound 1)

In two separate dropping funnels, a solution of tributylphosphine(0.00268 mol) in THF (20 ml) and a solution of ADDP (0.00155 mol) in THF(20 ml) were slowly simultaneously added to a solution of intermediate 2(0.00103 mol) in THF (20 ml) and DMF (2 m) chilled at 0° C. under anatmosphere of nitrogen. The reaction mixture was stirred for 4 hours atroom temperature, poured out into a 1N solution of aqueous hydrochloricacid and after 1 hour, the mixture was diluted with DCM. The precipitatewas filtered off, the organic phase was partitioned with a 10% aqueoussolution of potassium carbonate, dried (MgSO₄) and concentrated invacuo. The solid residue was sonicated in hot isopropanol, filtered off,washed with dry ether and dried in vacuo, yielding 0.16 g (44%) ofcompound (1).

Example B2 Preparation of6,4-(nitrilometheno)pyrimido[4,5-b][13,1,4,6]benzoxatriazacyclopentadecine,17-chloro-7,8,9,10,11,12,13,19-octahydro- (Compound 2)

In two separate dropping funnels, a solution of ADDP (0.00102 mol) inTHF (2 ml) and a solution of tributylphosphine (0.00177 mol) in THF (2ml) were slowly simultaneously added to a solution of intermediate 6(0.000681 mol) in THF (10 ml) and DMF (1.4 ml), and stirred at roomtemperature for 18 hours. Then, a solution of ADDP (0.000340 mol) in THF(0.7 mL) and a solution of tributylphosphine (0.000592 mol) in THF (0.7mL) were simultaneously added at room temperature for 2 hours. Themixture was hydrolyzed and the precipitate was filtered off, wash withwater then with isopropanol and the diethyl ether, and dried in vacuo,yielding 0.124 g (49%) of compound (2), melting point >260° C.

Example B3 Preparation of7H,21H-4,6-ethanediylidenepyrimido[4,5-b][15,1,4,6,10]benzoxatetraazacycloheptadecin-12(13H)-one,8,9,10,11,14,15-hexahydro- (Compound 3)

1-[bis(dimethylamino)methylene]-3-oxide-1H-benzotriazolium,hexafluoro-phosphate(1-) [94790-37-1] (0.00057 mol) was dissolved in DMF(20 ml) and stirred at room temperature. Intermediate (11) (0.00019 mol)was dissolved in DMF (10 ml) and N-ethyl-N-(1-methylethyl)-2-propanamine(0.00114 mol) was added. This solution was added slowly over a 2 hoursperiod to the first solution. The light-green solution was stirredovernight at room temperature. The solvent (DMF) was evaporated. Theresidue was purified by flash column chromatography, yielding compound(3).

Compounds that are prepared according to Example B34,6-ethanediylidenepyrimido[4,5- Compound 6b][1,4,6,10,13]benzopentaazacyclohexadecin-12(7H)- one,18-chloro-17-fluoro-8,9,10,11,13,14,15,20- octahydro--4,6-ethanediylidenepyrimido[4,5-b]pyrrolo[2,1- Compound 71][1,4,6,10,13]benzopentaazacyclohexadecin-12(7H)- one,20-chloro-19-fluoro-8,9,10,11,12a,13,14,15,17,22- decahydro--4,6-ethanediylidenepyrimido[4,5- Compound 8b][1,4,6,10,13]benzopentaazacyclohexadecin- 12(7H)-one,18-chloro-17-fluoro-8,9,10,11,13,14,15,20- octahydro-14-methyl-4,6-ethanediylidene-11H-pyrimido[4,5- Compound 9b][1,4,6,9,12]benzopentaazacyclopentadecin- 11-one,17-chloro-16-fluoro-7,8,9,10,12,13,14,19- octahydro-13-methyl-4,6-ethanediylidenepyrimido[4,5- Compound 10b][1,4,6,10,13]benzopentaazacyclohexadecin- 12(7H)-one,18-chloro-17-fluoro-8,9,10,11,13,14,15,20- octahydro-13-(2-4,6-ethanediylidenepyrimido[4,5- Compound 11b][1,4,6,10,13]benzopentaazacyclooctadecin- 15(16H)-one,20-bromo-7,8,9,10,11,12,13,14,17,22- decahydro-4,6-ethanediylidenepyrimido[4,5- Compound 12b][1,4,6,10,14]benzopentaazacyclooctadecin- 16(7H)-one,20-chloro-8,9,10,11,12,13,14,15,17,22- decahydro-4,6-ethanediylidene-7H-pyrimido[4,5- Compound 13b][1,4,6,10,14]benzopentaazacyclononadecin- 16(17H)-one,21-chloro-8,9,10,11,12,13,14,15,18,23- decahydro-4,6-ethanediylidenepyrimido[4,5- Compound 14b][1,4,6,10,13]benzopentaazacyclooctadecin- 15(16H)-one,20-chloro-7,8,9,10,11,12,13,14,17,22- decahydro-

Example B4 Preparation of7H,21H-6,4-(nitrilometheno)pyrimido[5,4-m][1,6,10,15]benzoxatriazacycloheptadecin-12(13H)-one,8,9,10,11,14,15-hexahydro- (Compound 4)

1-[bis(dimethylamino)methylene]-3-oxide-1H-benzotriazolium,hexafluoro-phosphate(1-) [94790-37-1] (0.00165 mol) was dissolved in DMF(40 ml) and stirred at room temperature. Intermediate (16) (0.00055 mol)was dissolved in DMF (20 ml) and N-ethyl-N-(1-methylethyl)-2-propanamine(0.0033 mol) was added. This solution was added slowly over a 2 hoursperiod to the first solution. The light-green solution was stirredovernight at room temperature. The solvent (DMF) was evaporated,yielding compound (4).

Compounds that are prepared according to Example B46,4-(nitrilometheno)pyrimido[4,5- Compound 15b][1,6,10,13]benzotetraazacyclohexadecin- 12(7H)-one,18-chloro-17-fluoro-8,9,10,11,13,14, 15,20-octahydro--6,4-(nitrilometheno)pyrimido[4,5-b]pyrrolo[2,1- Compound 161][1,6,10,13]benzotetraazacyclohexadecin- 12(7H)-one,20-chloro-19-fluoro-8,9,10,11,12a,13, 14,15,17,22-decahydro--6,4-(nitrilometheno)pyrimido[4,5- Compound 17b][1,6,10,13]benzotetraazacyclohexadecin- 12(7H)-one,18-chloro-17-fluoro-8,9,10,11,13,14,15,20- octahydro-14-methyl-6,4-(nitrilometheno)-11H-pyrimido[4,5- Compound 18b][1,6,9,12]benzotetraazacyclopentadecin-11-one,17-chloro-16-fluoro-7,8,9,10,12,13,14,19-octahydro- 13-methyl-6,4-(nitrilometheno)pyrimido[4,5- Compound 19b][1,6,10,13]benzotetraazacyclohexadecin-12(7H)-one,18-chloro-17-fluoro-8,9,10,11,13,14,15,20-octahydro-13-(2-methylpropyl)- 6,4-(nitrilometheno)pyrimido[4,5- Compound 20b][1,6,10,13]benzotetraazacyclooctadecin-15(16H)- one,20-bromo-7,8,9,10,11,12,13,14,17,22-decahydro-6,4-(nitrilometheno)pyrimido[4,5- Compound 21b][1,6,10,14]benzotetraazacyclooctadecin- 16(7H)-one,20-chloro-8,9,10,11,12,13,14,15,17, 22-decahydro-6,4-(nitrilometheno)-7H-pyrimido[4,5- Compound 22b][1,6,10,14]benzotetraazacyclononadecin- 16(17H)-one,21-chloro-8,9,10,11,12,13,14,15,18,23- decahydro-6,4-(nitrilometheno)pyrimido[4,5- Compound 23b][1,6,10,13]benzotetraazacyclooctadecin- 15(16H)-one,20-chloro-7,8,9,10,11,12,13,14,17,22- decahydro-

All other compounds can be prepared according to these procedures withthe remark that the cpds with Y being C₁₋₅ alkyl and X²/X¹ NH arecyclized under ring closing metathesis conditions using secondgeneration Grubbs catalysts of the dienes (see example B5 hereinafter)

Example B5 Preparation of4,6-ethanediylidenepyrimido[4,5-b][1,4,6,11]benzotetraazacyclotetradecine,16-chloro-15-fluoro-7,8,9,10,11,12,13,18-octahydro-12-methyl- (Compound5)

Intermediate (21) (1 equiv) was dissolved in a methanol/dioxane mixture(4/1), then catalyst Pt/C (0.3 equiv) was added and the reaction mixturewas stirred for 4 hours under H₂ atmosphere. The resulting mixture wasfiltered over a short celite pad and the filtrate was concentrated todryness. The obtained residue was dried under high vacuum, to afford0.029 g (60%) of pure compound (5).

Compound Identification

The compounds were identified by LC/MS using a gradient elution systemon a reversed phase HPLC. The compounds are identified by their specificretention time and their protonated molecular ion MH⁺ peak. The HPLCgradient was supplied by a Waters Alliance HT 2790 system with acolumnheater set at 40° C. Flow from the column was split to a Waters996 photodiode array (PDA) detector and a Waters-Micromass ZQ massspectrometer with an electrospray ionization source operated in positiveand negative ionization mode. Reversed phase HPLC was carried out on aXterra MS C18 column (3.5 μm, 4.6×100 mm) with a flow rate of 1.6ml/min. Three mobile phases (mobile phase A 95% 25 mM ammoniumacetate+5%acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol)were employed to run a gradient condition from 100% A to 50% B and 50% Cin 6.5 minutes, to 100% B in 1 minute, 100% B for 1 minute andreequilibrate with 100% A for 1.5 minutes. An injection volume of 10 μLwas used.

Mass spectra were acquired by scanning from 100 to 1000 in is using adwell time of 0.1 s. The capillary needle voltage was 3 kV and thesource temperature was maintained at 140° C. Nitrogen was used a thenebulizer gas. Cone voltage was 10 V for positive ionzation mode and 20V for negative ionization mode. Data acquisition was performed with aWaters-Micromass MassLynx-Openlynx data system.

TABLE retention time (RT in minutes) and molecular weight as the MH⁺Compound No. Rt MH+ 9 6.57 416 5 8.78 387 7 6.87 456 11  5.44 470 14 5.42 426 Int. 20 8.62 413 Int. 21 8.06 387 3 6.08 379 4 5.77 379

C. Pharmacological Examples Example C.1 In Vitro Inhibition of EGFR

The in vitro inhibition of EGFR was assessed using either the FlashPlate technology or the glass-fiber filter technology as described byDavies, S. P. et al., Biochem J. (2000), 351; p. 95-105. The Flash Platetechnology is generally described by B. A. Brown et al. in HighThroughput Screening (1997), p. 317-328. Editor(s): Devlin, John P.Publisher: Dekker, New York, N.Y.

In the Flash Plate EGFR kinase reaction assay, a kinase substrateconsisting of biotinylated poly(L-glutamic acid-L-tyrosine)(poly(GT)biotin), is incubated with the aforementioned protein in thepresence of (³³P) radiolabeled ATP. (³³P) phosphorylation of thesubstrate is subsequently measured as light energy emitted using astreptavidin-coated Flash Plate (PerkinElmer Life Sciences) by trappingand quantifying the binding of the biotin tagged and radiolabeledsubstrate.

Detailed Description

The EGFR kinase reaction is performed at 30° C. for 60 minutes in a96-well microtiter FlashPlate (PerkinElmer Life Sciences). For each ofthe tested compounds a full dose response 1.10⁻⁶M to 1.10⁻¹⁰M has beenperformed. IRESSA® and Tarceva™ (erlotinib) were used as referencecompounds. The 100 μl reaction volume contains 54.5 mM TrisHCl pH 8.0,10 mM MgCl₂, 100 μM Na₃VO₄, 5.0 μM unlabeled ATP, 1 mM DTT, 0.009% BSA,0.8 μCi AT³³P, 0.35 μg/well poly(GT)biotin and 0.5 μg EGFR-kinasedomain/well.

The reaction is stopped by aspirating the reaction mixture and washingthe plate 3× with 200 μl wash/stop buffer (PBS+100 mM EDTA). After thefinal wash step 200 μl of wash/stop buffer was added to each well andthe amount of phosphorylated (³³P) Poly(GT)biotin determined by counting(30 sec/well) in a microtiterplate scintillation counter.

In the glass-fiber filter technology EGFR kinase reaction assay, akinase substrate consisting of poly(L-glutamic acid-L-tyrosine)(poly(GT)), is incubated with the aforementioned protein in the presenceof (³³P) radiolabeled ATP. (³³P) Phosporylation of the substrate issubsequently measured as radioactivity bound on a glassfiber-filter.

Detailed Description

The EGFR kinase reaction is performed at 25° C. for 10 minutes in a96-well microtiterplate. For each of the tested compounds a full doseresponse 1.10⁻⁶M to 1.10⁻¹⁰M has been performed. IRESSA® and Tarceva™(erlotinib) were used as reference compounds. The 25 μl reaction volumecontains 60 mM TrisHCl pH 7.5, 3 mM MgCl₂, 3 mM Mn Cl₂, 3 μM Na₃VO₄, 50μg/ml PEG20000, 5.0 μM unlabeled ATP, 1 mM DTT, 0.1 μCi AT³³P, 62.5ng/well poly(GT) and 0.5 μg EGFR-kinase domain/well.

The reaction is stopped by adding 5 μl of a 3% phosphoric acid solution.10 μl of the reaction mixture is then spotted onto a Filtermat A filter(Wallac) and washed 3 times for 5 min. in 75 mM phosphoric acid and 1time for 5 min. in methanol prior to drying and quantification on theTyphoon (Amersham) using a LE phosphorage storage screen.

Example C.2 Serum Starved Proliferation Assay on the Ovarian CarcinomaSKOV3 Cells

The ovarian carcinoma cell line (SKOV3) was used in an epidermal growthfactor stimulated cell proliferation assay, to assess the inhibitoryeffect of the compounds on EGF in whole cells.

In a first step the SKOV3 cells were incubated for 24 hours in thepresence of 10% FCS serum. In the second step the cells were incubatedwith the compounds to be tested in a serum free condition (37° C. and 5%(v/v) CO₂) and subsequently stimulated for 72 hours with EGF at a finalconcentration of 100 ng/ml. The effect of the compounds on the EGFstimulation was finally assessed in a standard MTT cell viability assay.

The following table provides the pIC50 values of the compounds accordingto the invention, obtained using the above mentioned kinase assays.

In vitro kinase In vitro kinase Compound activity assay.(C1): SKOV3 cell(C2): Intermediate activity assay.(C1): SKOV3 cell (C2): number IC50 innM IC50 in μM number IC50 in nM IC50 in μM 2 8.2 5.5 2 8.5 <5.0 3 8.46.1 1 8.3 6.23 4 8.3 5.8 6 8.4 6.0

D. Composition Examples

The following formulations exemplify typical pharmaceutical compositionssuitable for systemic administration to animal and human subjects inaccordance with the present invention.

“Active ingredient” (A.I.) as used throughout these examples relates toa compound of formula (I), (XXXI) or a pharmaceutically acceptableaddition salt thereof.

Example D.1 Film-Coated Tablets Preparation of Tablet Core

A mixture of A.I. (100 g), lactose (570 g) and starch (200 g) was mixedwell and thereafter humidified with a solution of sodium dodecyl sulfate(5 g) and polyvinyl-pyrrolidone (10 g) in about 200 ml of water. The wetpowder mixture was sieved, dried and sieved again. Then there was addedmicrocrystalline cellulose (100 g) and hydrogenated vegetable oil (15g). The whole was mixed well and compressed into tablets, giving 10.000tablets, each comprising 10 mg of the active ingredient.

Coating

To a solution of methyl cellulose (10 g) in denaturated ethanol (75 ml)there was added a solution of ethyl cellulose (5 g) in CH₂Cl₂ (150 ml).Then there were added CH₂Cl₂ (75 ml) and 1,2,3-propanetriol (2.5 ml).Polyethylene glycol (10 g) was molten and dissolved in dichloromethane(75 ml). The latter solution was added to the former and then there wereadded magnesium octadecanoate (2.5 g), polyvinyl-pyrrolidone (5 g) andconcentrated color suspension (30 ml) and the whole was homogenated. Thetablet cores were coated with the thus obtained mixture in a coatingapparatus.

1-13. (canceled)
 14. A method of treating a cell proliferative disorder, the method comprising administering to an animal in need of such treatment a therapeutically effective amount of a compound having the formula

the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein a¹-a²=a³-a⁴ represents a divalent radical selected from N—CH═CH—CH, N—CH═N—CH or CH—CH═N—CH; Z represents O, NH or S; Y represents —C₃₋₉alkyl-, —C₃₋₉alkenyl-, —C₁₋₅alkyl-oxy-C₁₋₅alkyl-, —C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-, —C₁₋₅alkyl-NR¹⁴—CO—C₁₋₅alkyl-, —C₁₋₅alkyl-CO—NR¹⁵—C₁₋₅alkyl-, —C₁₋₆alkyl-CO—NH—, —C₁₋₆alkyl-NH—CO—, —CO—NH—C₁₋₆alkyl-, —NH—CO—C₁₋₆alkyl-, —CO—C₁₋₇alkyl-, —C₁₋₇alkyl-CO—, C₁₋₆alkyl-CO—C₁₋₆alkyl; X¹ represents a direct bond, O, —O—C₁₋₂alkyl-, CO, —CO—C₁₋₂alkyl-, NR¹¹, —NR¹¹—C₁₋₂alkyl-, NR¹⁶—CO—, NR¹⁶—CO—C₁₋₂alkyl-, —O—N═CH— or C₁₋₂alkyl; X² represents a direct bond, O, —O—C₁₋₂alkyl-, CO, —CO—C₁₋₂alkyl-, NR¹², NR¹²—C₁₋₂alkyl-, NR¹⁷—CO—, NR¹⁷—CO—C₁₋₂alkyl-, Het²⁰-C₁₋₂alkyl-, —O—N═CH— or C₁₋₂alkyl; R¹ represents hydrogen, cyano, halo, hydroxy, formyl, C₁₋₆alkoxy-, C₁₋₆alkyl-, C₁₋₆alkoxy- substituted with halo, C₁₋₄alkyl substituted with one or where possible two or more substituents selected from hydroxy or halo; R² represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-, Het¹⁶-carbonyl-, C₁₋₄alkyloxycarbonyl-, C₁₋₄alkylcarbonyl-, aminocarbonyl-, mono- or di(C₁₋₄alkyl)aminocarbonyl-, Het¹, formyl, C₁₋₄alkyl-, C₂₋₆alkynyl-, C₃₋₆cycloalkyl-, C₃₋₆cycloalkyloxy-, C₁₋₆alkoxy-, Ar⁵, Ar¹-oxy-, dihydroxyborane, C₁₋₆alkoxy- substituted with halo, C₁₋₄alkyl substituted with one or where possible two or more substituents selected from halo, hydroxy or NR⁵R⁶, C₁₋₄alkylcarbonyl- wherein said C₁₋₄alkyl is optionally substituted with one or where possible two or more substituents selected from hydroxy or C₁₋₄alkyl-oxy-; R³ represents hydrogen, C₁₋₄alkyl, cyano or C₁₋₄alkyl substituted with one or more substituents selected from halo, C₁₋₄alkyloxy-, amino-, mono- or di(C₁₋₄alkyl)amino-, C₁₋₄alkyl-sulfonyl- or phenyl; R⁴ represents hydrogen, hydroxy, Ar³-oxy, Ar⁴—C₁₋₄alkyloxy-, C₁₋₄alkyloxy-, C₂₋₄alkenyloxy- optionally substituted with Het¹² or R⁴ represents C₁₋₄alkyloxy substituted with one or where possible two or more substituents selected from C₁₋₄alkyloxy-, hydroxy, halo, Het²-, —NR⁷R⁸, -carbonyl-NR⁹R¹⁰ or Het³-carbonyl-; R⁵ and R⁶ are each independently selected from hydrogen or C₁₋₄alkyl; R⁷ and R⁸ are each independently selected from hydrogen, C₁₋₄alkyl, Het⁸, aminosulfonyl-, mono- or di(C₁₋₄alkyl)-aminosulfonyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-, hydroxycarbonyl-C₁₋₄alkyl-, C₃₋₆cycloalkyl, Het⁹-carbonyl-C₁₋₄-alkyl-, Het¹⁹-carbonyl-, polyhydroxy-C₁₋₄alkyl-, Het¹¹-C₁₋₄alkyl- or Ar²—C₁₋₄alkyl-; R⁹ and R¹⁹ are each independently selected from hydrogen, C₁₋₄alkyl, C₃₋₆cycloalkyl, Het⁴, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl- or polyhydroxy-C₁₋₄alkyl-; R¹¹ represents hydrogen, C₁₋₄alkyl, Het⁵, Het⁶-C₁₋₄alkyl-, C₂₋₄alkenylcarbonyl- optionally substituted with Het⁷-C₁₋₄alkylaminocarbonyl-, C₂₋₄alkenylsulfonyl-, C₁₋₄alkyloxyC₁₋₄alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C₁₋₄alkyloxy-; R¹² represents hydrogen, C₁₋₄alkyl, C₁₋₄alkyl-oxy-carbonyl-, Het¹⁷, Het¹⁸-C₁₋₄alkyl-, C₂₋₄alkenylcarbonyl- optionally substituted with Het¹⁹-C₁₋₄alkylaminocarbonyl-, C₂₋₄alkenylsulfonyl-, C₁₋₄alkyloxyC₁₋₄alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C₁₋₄-alkyloxy-; R¹³ represents hydrogen, C₁₋₄alkyl, Het¹³, Het¹⁴-C₁₋₄alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C₁₋₄alkyloxy-; R¹⁴ and R¹⁵ are each independently selected from hydrogen, C₁₋₄alkyl, Het¹⁵-C₁₋₄alkyl- or C₁₋₄alkyloxyC₁₋₄alkyl-; R¹⁶ and R¹⁷ are each independently selected from hydrogen, C₁₋₄alkyl, Het²¹-C₁₋₄alkyl- or C₁₋₄alkyloxyC₁₋₄alkyl-; Het¹ represents a heterocycle selected from piperidinyl, morpholinyl, piperazinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het¹ is optionally substituted with one or where possible two or more substituents selected from amino, C₁₋₄alkyl, hydroxy-C₁₋₄alkyl-, phenyl, phenyl-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl- mono- or di(C₁₋₄alkyl)amino- or amino-carbonyl-; Het² represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl or dithianyl wherein said Het² is optionally substituted with one or where possible two or more substituents selected from hydroxy, halo, amino, C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl-oxy-C₁₋₄-alkyl-, mono- or di(C₁₋₄alkyl)amino-, mono- or di(C₁₋₄alkyl)amino-C₁₋₄alkyl-, aminoC₁₋₄alkyl-, mono- or di(C₁₋₄alkyl)amino-sulfonyl-, aminosulfonyl-; Het³, Het⁴ and Het⁸ each independently represent a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het³, Het⁴ or Het⁸ is optionally substituted with one or where possible two or more substituents selected from hydroxy-, amino-, C₁₋₄alkyl-, C₃₋₆cycloalkyl-C₁₋₄alkyl-, aminosulfonyl-, mono- or di(C₁₋₄alkyl)aminosulfonyl or amino-C₁₋₄alkyl-; Het⁵ represent a heterocycle selected from pyrrolidinyl or piperidinyl wherein said heterocycle is optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het⁶ and Het⁷ each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl wherein said Het⁶ and Het⁷ are optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het⁹ and Het¹⁰ each independently represent a heterocycle selected from furanyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het⁹ or Het¹⁰ is optionally substituted C₁₋₄alkyl, C₃₋₆cycloalkyl-C₁₋₄alkyl- or amino-C₁₋₄alkyl-; Het¹¹ represents a heterocycle selected from indolyl or

Het¹² represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl or dithianyl wherein said Het¹² is optionally substituted with one or where possible two or more substituents selected from hydroxy, halo, amino, C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-, hydroxy-C₁₋₄alkyl-oxy-C₁₋₄-alkyl-, mono- or di(C₁₋₄alkyl)amino- or mono- or di(C₁₋₄alkyl)amino-C₁₋₄alkyl-; Het¹³ represent a heterocycle selected from pyrrolidinyl or piperidinyl wherein said heterocycle is optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄allyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het¹⁴ represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl wherein said heterocycle is optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het¹⁵ and Het²¹ each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl wherein said Het¹⁵ or Het²¹ are optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het¹⁶ represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl, 1,3,2-dioxaborolane or piperidinyl wherein said heterocycle is optionally substituted with one or more substituents selected from C₁₋₄alkyl; Het¹⁷ represent a heterocycle selected from pyrrolidinyl or piperidinyl wherein said heterocycle is optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het¹⁸ and Het¹⁹ each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl wherein said Het¹⁸ and Het¹⁹ are optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; Het²⁰ represents a heterocycle selected from pyrrolidinyl, 2-pyrrolidinyl, piperidinyl, piperazinyl or pyrazolidinyl wherein said heterocycle is optionally substituted with one or where possible two or more substituents selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy-C₁₋₄alkyl-, C₁₋₄alkyloxyC₁₋₄alkyl or polyhydroxy-C₁₋₄alkyl-; and Ar¹, Ar², Ar³, Ar⁴ and Ar⁵ each independently represent phenyl optionally substituted with cyano, C₁₋₄alkylsulfonyl-, C₁₋₄alkylsulfonylamino-, aminosulfonylamino-, hydroxy-C₁₋₄-alkyl, aminosulfonyl-, hydroxy-, C₁₋₄alkyloxy- or C₁₋₄alkyl.
 15. The method according to claim 14 wherein; Z represents NH; Y represents —C₃₋₉alkyl-, —C₂₋₉alkenyl-, —C₁₋₅alkyl-oxy-C₁₋₅alkyl-, —C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-, —C₁₋₅alkyl-NR¹⁴—CO—C₁₋₅alkyl-, —C₁₋₆alkyl-NH—CO—, —CO—C₁₋₇alkyl-, —C₁₋₇alkyl-CO— or C₁₋₆alkyl-CO—C₁₋₆alkyl; X¹ represents O, —O—C₁₋₂alkyl-, —O—N═CH—, NR¹¹ or —NR¹¹—C₁₋₂alkyl-; in a particular embodiment X¹ represents a direct bond, C₁₋₂alkyl-, —O—C₁₋₂alkyl, —NR¹¹—, —O— or —O—CH₂—; X² represents a direct bond, O, —O—C₁₋₂alkyl-, —O—N═CH—, NR¹⁷—CO—, NR¹⁷—CO—C₁₋₂alkyl-, C₁₋₂alkyl, Het²⁰-C₁₋₂alkyl-, NR¹² or NR¹²—C₁₋₂alkyl-; in a particular embodiment X² represents a direct bond, C₁₋₂alkyl-, —O—C₁₋₂alkyl, NR¹⁷—CO—, NR¹⁷—CO—C₁₋₂alkyl-, Het²⁰-C₁₋₂alkyl-, —O— or —O—CH₂—; R¹ represents hydrogen, cyano, halo or hydroxy, preferably halo; R² represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-, C₁₋₄alkyloxycarbonyl-, Het¹⁶-carbonyl-, C₁₋₄alkyl-, C₂₋₆alkynyl-, Ar⁵ or Het¹; R³ represents hydrogen; R⁴ represents hydrogen, hydroxy, C₁₋₄alkyloxy-, Ar⁴—C₁₋₄alkyloxy or R⁴ represents C₁₋₄alkyloxy substituted with one or where possible two or more substituents selected from C₁₋₄alkyloxy- or Het²-; R¹¹ represents hydrogen, C₁₋₄alkyl- or C₁₋₄alkyl-oxy-carbonyl-; R¹² represents hydrogen, C₁₋₄alkyl- or C₁₋₄alkyl-oxy-carbonyl-; R¹³ represents hydrogen or Het¹⁴-C₁₋₄alkyl, in particular morpholinyl-C₁₋₄alkyl; R¹⁴ represents hydrogen or C₁₋₄alkyl; R¹⁷ represents hydrogen, C₁₋₄alkyl-, Het²¹-C₁₋₄alkyl or C₁₋₄alkyl-oxy-C₁₋₄alkyl; in particular R¹⁷ represents hydrogen or C₁₋₄alkyl; Het¹ represents thiazolyl optionally substituted with amino, C₁₋₄alkyl, hydroxy-C₁₋₄alkyl-, phenyl, phenyl-C₁₋₄alkyl-, C₁₋₄alkyl-oxy-C₁₋₄alkyl-, mono- or di(C₁₋₄alkyl)amino- or amino-carbonyl-; Het² represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het² is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or C₁₋₄alkyl-; Het¹⁴ represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het¹⁴ is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or C₁₋₄alkyl-; Het¹⁶ represents a heterocycle selected from piperidinyl, morpholinyl or pyrrolidinyl; Het²⁰ represents a heterocycle selected from pyrrolidinyl, 2-pyrrolidinyl or piperidinyl; Het²¹ represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het²¹ is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or C₁₋₄alkyl-; Ar⁴ represents phenyl optionally substituted with cyano, hydroxy-, C₁₋₄alkyloxy or C₁₋₄alkyl; Ar⁵ represents phenyl optionally substituted with cyano, hydroxy, C₁₋₄alkyloxy or C₁₋₄alkyl.
 16. The method according to claim 14 wherein; Z represents NH; Y represents —C₃₋₉alkyl-, —C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-, —C₁₋₅alkyl-NR¹⁴—CO—C₁₋₅alkyl-, —C₁₋₆alkyl-NH—CO— or —CO—NH—C₁₋₆alkyl-; X¹ represents —O—, —NR¹¹—, —NR¹⁶—CO—, or —NR¹⁶—CO—C₁₋₂alkyl-; X² represents a direct bond, —C₁₋₂alkyl-, —O—C₁₋₂alkyl, —O—, —O—CH₂— or Het²⁰-C₁₋₂alkyl-; R¹ represents hydrogen or halo; R² represents hydrogen, cyano, halo, hydroxycarbonyl-, C₁₋₄alkyloxycarbonyl-, Het¹⁶-carbonyl- or Ar⁵; in particular R² represents hydrogen or halo; R³ represents hydrogen; R⁴ represents hydrogen, hydroxy, C₁₋₄alkyloxy-, Ar⁴—C₁₋₄alkyloxy or R⁴ represents C₁₋₄alkyloxy substituted with one or where possible two or more substituents selected from C₁₋₄alkyloxy- or Het²-; R¹¹ represents hydrogen; R¹² represents hydrogen, C₁₋₄alkyl- or C₁₋₄alkyl-oxy-carbonyl-; R¹³ represents hydrogen or Het¹⁴-C₁₋₄alkyl, in particular hydrogen or morpholinyl-C₁₋₄alkyl; Het² represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het² is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or C₁₋₄alkyl-; Het¹⁴ represents morpholinyl; Het¹⁶ represents a heterocycle selected from morpholinyl or pyrrolidinyl; Het²⁰ represents pyrrolidinyl or piperidinyl; Ar⁴ represents phenyl; Ar⁵ represents phenyl optionally substituted with cyano.
 17. The method according to claim 14 wherein the R¹ substituent is at position 4′, the R² substituent is at position 5′, the R³ substituent is at position 3 and the R⁴ substituent at position 7 of the structure of formula (I).
 18. The method according to claim 14 wherein a¹-a²=a³-a⁴ represents N—CH═CH—CH.
 19. The method according to claim 14 wherein a¹-a²=a³-a⁴ represents N—CH═N—CH.
 20. The method according to claim 14 wherein a¹-a²=a³-a⁴ represents CH—CH═N—CH.
 21. A method of treating a cell proliferative disorder, the method comprising administering to an animal in need of such treatment a therapeutically effective amount of a compound having the formula

the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein a¹-a²=a³-a⁴ represents a divalent radical selected from N—CH═CH—CH or N—CH═N—CH; Y represents —C₃₋₉alkyl-, —C₁₋₅alkyl-NR¹³—C₁₋₅alkyl-, —C₁₋₆alkyl-NH—CO— or —CO—NH—C₁₋₆alkyl-; R¹ represents hydrogen or halo; R² represents hydrogen, cyano, halo, hydroxycarbonyl-, C₁₋₄alkyloxycarbonyl-, Het¹⁶-carbonyl- or Ar⁵; R⁴ represents hydroxy, C₁₋₄alkyloxy-, Ar⁴—C₁₋₄alkyloxy or R⁴ represents C₁₋₄alkyloxy substituted with one or where possible two or more substituents selected from C₁₋₄alkyloxy- or Het²-; R¹¹ represents hydrogen; R¹³ represents Het¹⁴-C₁₋₄alkyl; Het² represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het² is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or C₁₋₄alkyl-; Het¹⁴ represents morpholinyl; Het¹⁶ represents a heterocycle selected from morpholinyl or pyrrolidinyl; Ar⁴ represents phenyl; Ar⁵ represents phenyl optionally substituted with cyano. 